KR20140016345A - Bispecific binding molecules binding to dll4 and ang2 - Google Patents

Abstract

The present invention provides bispecific binding molecules which bind Dll4 and Ang2, preferably in the form of immunoglobulin single variable domains, such as VHH and domain antibodies, pharmaceutical compositions containing them, and Dll4- and / or Ang2-mediated effects on angiogenesis. And their use in the treatment of diseases associated with. The present invention also relates to a nucleic acid encoding a bispecific binding molecule, a host cell, and a method for producing the same.

Description

Bispecific binding molecule that binds to Dll4 and Ang2 {BISPECIFIC BINDING MOLECULES BINDING TO DLL4 AND ANG2}

FIELD OF THE INVENTION The present invention relates to the field of human therapy, and in particular, to cancer therapy and drugs and compositions useful for such therapy.

When the tumor reaches a critical size of about 1 mm ³ , the tumor may grow further depending on angiogenesis, which maintains a blood supply with oxygen and nutrients. Anti-angiogenic therapy has become an important treatment in many types of tumors. These therapies are focused on blocking the VEGF pathway (Ferrara et al., Nat Rev Drug Discov. 2004 May; 3 (5): 391-400) by neutralizing VEGF (Avastin) or its receptors (Sutent and Sorafinib). Recent mouse studies have shown that the ligand of the Tie2 receptor, Angiopoietin2 (Ang2), regulates vascular remodeling by functioning other angiogenic factors such as VEGF. Ang2 is expressed mainly by endothelial cells, is strongly induced by hypoxia and other angiogenesis factors and has been shown to regulate tumor angiogenesis so that blood vessels can respond to VEGF and FGF2 (Augustin et al., Nat Rev Mol Cell Biol. 2009 Mar; 10 (3): 165-77). In line with this role, deletion or inhibition of Ang2 reduced angiogenesis (Falcon et al., Am J Pathol. 2009 Nov; 175 (5): 2159-70). High Ang2 serum concentrations have been reported in patients with colorectal cancer, NSCLC and melanoma (Goede et al., Br J Cancer. 2010 Oct 26; 103 (9): 1407-14), (Park et al., Chest. 2007 Jul 132 (1): 200-6), (Helfrich et al., Clin Cancer Res. 2009 Feb 15; 15 (4): 1384-92). Ang2 serum concentrations in CRC cancers are associated with treatment response to anti-VEGF therapy.

The Ang-Tie system consists of two receptors (Tie1 and Tie2) and three ligands (Ang1, Ang2 and Ang4) (Augustin et al., Nat Rev Mol Cell Biol. 2009 Mar; 77.). Tie2, Ang1 and Ang2 are the best studied of these species, Tie1 is an orphan receptor, and the role of Ang4 in vascular remodeling still remains to be elucidated. Ang2 and Ang1 mediate the antagonism of Tie2 binding and activation. Ang2 mediated Tie2 activation results in induction of endothelial cell activation, peripheral cell degradation, vascular leakage, and vessel sprouting. In contrast to Ang2, Ang1 signaling maintains endothelial cell quiescence by maintaining vascular integrity by supplementing surrounding cells.

Angiopoietin 2 (Ang2) is a 66 kDa secreting ligand for Tie2 receptor tyrosine kinase (Augustin et al., Nat Rev Mol Cell Biol. 2009 Mar; 10 (3): 165-77). Ang2 consists of the N-terminal's coiled coil domain and the C-terminal fibrinogen-like domain, the latter of which is required for Tie2 interaction. Ang2 is mainly expressed by endothelial cells and is strongly induced by other angiogenic factors including hypoxia and VEGF. Tie2 is found in endothelial cells, hematopoietic stem cells and tumor cells. Ang2-Tie2 has been shown to modulate tumor angiogenesis to allow blood vessels to respond to VEGF and FGF2.

In vitro, Ang2 appeared to act as gentle mitogen, chemoattractant, and tube forming inducer in human endothelial cells (HUVEC). Ang2 induces tyrosine phosphorylation of Tie2 expressed ectopically in fibroblasts and promotes lower signaling events such as phosphorylation of ERK-MAPK, AKT and FAK within HUVEC. The antagonistic role of Ang2 in Ang1-induced endothelial response has been described.

Ang2 deficiency has been demonstrated to cause severe lymph patterned binding in mice. Ang2-deficient mice have persistent vascular defects in the retina and kidney, although loss of Ang2 may be unnecessary for embryonic vascular development. Together with the dynamic pattern of Ang2 expression at neovascularization sites (eg, ovaries), this finding suggests that Ang2 performs the action of other angiogenic factors such as VEGF to regulate vascular remodeling.

Ang2-Tie2 systems play a crucial role in the late stages of angiogenic switch and tumor angiogenesis. Ang2 expression is strongly upregulated in tumor-associated endothelium. A decrease in tumor growth was observed in Ang2 deficient mice, particularly when implanted during the early stages of tumor growth. Therapeutic blocking of Ang2 by Ang2 mAbs has shown broad efficacy in various tumor xenograft models.

As summarized in US 2008/0014196, neovascularization is associated with the development of numerous disorders, including solid tumors and metastases.

In the case of tumor growth, neovascularization appears to be important for the transition from hyperplasia to neoplasia and for nourishing tumor growth and metastasis. According to Folkman et al. [Nature 339-58 (1989)], the growth of tumor cells in comparison with normal cells can thus be obtained. Thus, anti-angiogenic therapy has become an important treatment for various types of tumors. These therapies focus on blocking the VEGF pathway (Ferrara et al., Nat Rev Drug Discov. 2004 May; 3 (5): 391-400).

Notch signaling pathways are important for cell-cell communication and are involved in gene regulation mechanisms that regulate numerous cell differentiation processes during embryonic development and in adults. Notch signaling is dysregulated in many cancers, such as T-cell acute lymphocytic leukemia and solid tumors (Sharma et al. 2007, Cell Cycle 6 (8): 927-30; Shih et al., Cancer Res. 2007 Mar 1; 67 (5): 1879-82).

Dll4 (or Delta like 4 or delta-like ligand 4) is one of the delta groups of the Notch ligand. The extracellular domain of Dll4 consists of an N-terminal domain, a Delta / Serrate / Lag-2 (DSL) domain, and a tandem of eight epidermal growth factor (EGF) -like repeats. In general, EGF domains include amino acid residues 218-251 (EGF-1; domain 1), 252-282 (EGF-2; domain 2), 284-322 (EGF-3; domain 3), 324-360 (EGF-4 Domain 4), and 362-400 (EGF-5; domain 5), having a DSL domain of about 173-217 amino acid residues of hDll4 and an N-terminal domain of amino acid residues of about 27-172 ( WO 2008/076379).

Dll4 has been reported to exhibit highly selective expression by the vascular endothelium, especially in the arterial endothelium (Shutter et. al . (2000) Genes Develop. 14: 1313-1318). Recent mouse studies have shown that Dll4 is induced by VEGF and is a negative feedback regulator that controls vascular germination and branching. In agreement with this role, deletion or inhibition of Dll4 causes excessive neovascularization (Scehnet et. al . , Blood. 2007 Jun 1; 109 (11): 4753-60). This uninhibited neovascularization paradoxically reduces tumor growth due to the formation of non-productive vasculature even in tumors resistant to anti-VEGF therapy (Thurston et al. al . , Nat Rev Cancer. 2007 May; 7 (5): 327-31; WO 2007/070671; Noguera-Troise et al . , Nature. 2006 Dec 21; 444 (7122)). In addition, inhibition of VEGF and Dll4 together has been shown to provide superior anti-tumor activity compared to anti-VEGF alone in xenograft models of multiple tumor types (Noguera-Troise et al. , Nature. 2006 Dec 21; 444 (7122). 1032-7; Ridgway et al . , Nature. 2006 Dec 21; 444 (7122): 1083-7).

As a result, Dll4 is considered to be a promising target of cancer therapy, and various biological compounds in (pre) clinical development that target Dll4 are described as follows: REGN-421 (= SAR153192; Regeneron, Sanofi-). Aventis; WO2008076379) and OPM-21M18 (OncoMed) (Hoey et al . , Cell Stem Cell. 2009 Aug 7; 5 (2): 168-77), both whole human Dll4 antibodies; YW152F (Genentech), humanized Dll4 antibody (Ridgway et al . , Nature. 2006 Dec 21; 444 (7122): 1083-7); Dll4-Fc (Regeneron, Sanofi-Aventis), a recombinant fusion protein consisting of the extracellular region of Dll4 and the Fc region of human IgG1 (Noguera-Troise et al . , Nature. 2006 Dec 21; 444 (7122)).

However, state-of-the-art monoclonal antibodies (MAbs) and fusion proteins have some disadvantages in terms of their therapeutic applications: they must be stored at almost freezing temperatures to prevent degradation. In addition, they are not suitable for oral administration because they are rapidly degraded in the digestive tract. Another important limitation of MAbs in cancer therapy is poor transport, which results in low concentrations and inability to target all cells in the tumor.

It is an object of the present invention to provide novel anti-angiogenic binding molecules for human therapy.

It is a further object of the present invention to provide a method for the prevention, treatment, alleviation and / or diagnosis of such diseases, disorders or conditions comprising the use and / or administration of such binding molecules and compositions comprising them. In particular, it is an object of the present invention to provide pharmacologically active binding molecules, compositions and / or methods which provide advantages over the agents, compositions and / or methods currently used and / or known in the art. These advantages include, for example, improved therapeutic and / or pharmacological properties and / or other advantageous properties, especially when compared to common antibodies or fragments thereof as described above.

According to a first aspect, there is provided a bispecific binding molecule, preferably a bispecific immunoglobulin, preferably an immunoglobulin single variable domain, such as a VHH and domain antibody, which at least contains at least one DLL4-binding component in a single molecule. It contains one Ang2-binding component. Bispecific binding molecules may preferably comprise further binding components, preferably binding components to serum albumin.

More specifically, the bispecific binding molecules of the present invention essentially comprise (i) at least one Dll4 binding component that specifically binds to at least one Dll4 epitope and (ii) at least specifically bind to at least one Ang2 epitope. One Ang2 binding component, wherein the components are linked to each other in such a way that they bind to Dll4 and Ang2 at the same time or they bind to Dll4 or Ang2 at once.

According to a preferred aspect of the invention, the two components independently of one another have one or more immunoglobulin single variable domains which may be different types of immunoglobulin single variable domains such as VHH or domain antibodies, and / or VL domains as defined herein. However, each of these immunoglobulin single variable domains will bind to an antigen, ie Dll4 or Ang2, respectively.

According to a preferred embodiment, the immunoglobulin single variable domains are of the same kind, in particular all immunoglobulin single variable domains are VHH or domain antibodies.

According to a particularly preferred embodiment, all immunoglobulin single variable domains are VHH, preferably humanized (or “sequence optimized” as defined herein) VHH. Accordingly, the present invention relates to bispecific binding molecules comprising anti-Dll4 VHH (optionally humanized or sequence optimized) and anti-Ang2 VHH (optionally humanized or sequence optimized).

However, it is clear to those skilled in the art that the present disclosure can be similarly applied to bispecific binding molecules comprising other anti-Dll4 or anti-Ang2 immunoglobulin single variable domains, such as domain antibodies.

In another aspect, the present invention relates to a nucleic acid encoding a bispecific binding molecule of the present invention and a host cell containing the same.

The invention also relates to products or compositions containing or comprising at least one bispecific binding molecule of the invention and optionally one or more additional components of the composition.

The invention also relates to methods of making or producing the bispecific binding molecules, nucleic acids, host cells, products and compositions described herein.

The invention also relates to the application and use of the bispecific binding molecules, nucleic acids, host cells, products and compositions described herein, as well as to methods of preventing and / or treating diseases and disorders that can be modulated by Dll4 inhibition.

The Ang2 binding component of the bispecific binding molecule according to the invention has been found to bind Ang2 with a titer of at least 5,000 times, preferably 10,000 times greater than Ang1 or Ang4. This will significantly prevent activation blocking of Ang1 mediated signaling, corresponding to the intended anti-angiogenic effect.

The DLL4 binding component of the bispecific binding molecule according to the invention was found to bind DLL4-A with Dll1, Jagged1, and preferably also with at least 1,000 times more affinity for Jagged2. This selectivity prevents unwanted side effects.

In a preferred embodiment, bispecific binding molecules of the invention are provided as linked VHH domains. These molecules are much smaller than common antibodies, and thus have the ability to penetrate deeper into tumors than common antibodies. This advantage is further evident by the specific sequences described herein after being freed at the glycosylation site.

In addition, the bispecific nature (Dll4- and Ang2-binding components in one molecule) makes the tumor permeability of both functional groups essentially equivalent, whereby the beneficial effect of the combined antagonism of Dll4 and Ang2 is evident of tumor permeation. Will be provided within full depth. This is advantageous over the combination of individual antagonists for these targets because the penetration depth of the individual antagonists always changes to some extent. Another advantage of the preferred bispecific binding molecules of the present invention is their increased serum half-life due to serum albumin binding components such as the serum albumin binding molecules described herein.

These and other aspects, embodiments, advantages and applications of the present invention will become more apparent from the following detailed description.

Justice

Unless otherwise indicated or defined, all terms used have their ordinary meaning in the art, as would be apparent to those skilled in the art. For example, reference can be made to the standard background documents quoted here, as well as the following standard handbooks: Sambrook et al., "Molecular Cloning: A Laboratory Manual" (2nd Ed.), Vols. 1-3, Cold Spring Harbor Laboratory Press (1989); Lewin, "Genes IV ", Oxford University Press, New York, (1990), and Roitt et al . ^{, "Immunology" (2 nd Ed} .), Gower Medical Publishing, London, New York (1989). Also, unless otherwise indicated, all methods, steps, techniques and operations not specifically described in detail can be carried out and carried out in a manner known per se to those skilled in the art. In addition, reference may be made, for example, to the standard handbook, the general background art mentioned above, and the additional references cited therein.

The term "bispecific binding molecule" refers to a molecule comprising at least one Ang2-binding molecule (or "Ang2-binding component") and at least one Dll4-binding molecule (or "Dll4-binding component"). Bispecific binding molecules may contain more than one Ang2-binding molecule and / or more than one Dll4-binding molecule, ie the moiety moiety in which the bispecific binding molecule binds to Ang2 or Dll4, ie its "Ang2-binding component". A biparatopic Ang2-binding molecule and / or a biparatope Dll4- (as defined below) to each of the "(or anti-Ang2 component) or" Dll4-binding component "(or anti-Dll4 component) In the case of containing a binding molecule. However, the term "bispecific" in the present invention should not be construed as excluding other binding components having binding specificities for molecules other than Dll4 and Ang2 in bispecific binding molecules. Non-limiting examples of such additional binding components are binding components that bind to serum albumin.

Unless otherwise indicated, the terms "immunoglobulin" and "immunoglobulin sequence ", whether used herein to refer to heavy chain antibodies or common 4-chain antibodies, An antibody, its individual chains, all of its parts, domains or fragments (including, but not limited to, VHH domains or antigen-binding domains or fragments such as each of the VH / VL domains). Also, the term "sequence" (as in the terms "immunoglobulin sequence", "antibody sequence", "(single) variable domain sequence", "VHH sequence" or "protein sequence" , Unless the context requires a more limited description, it should generally be understood to include the relevant amino acid sequence as well as the nucleic acid sequence or nucleotide sequence encoding it.

The term "domain" (of a polypeptide or protein) used herein refers to a folded protein structure having the ability to retain its tertiary structure independently of the rest of the protein. In general, the domain is responsible for the individual functional properties of the protein, and in many cases can be added to, removed from, or transferred to another protein without loss of function of the remaining protein and / or domain.

As used herein, the term "immunoglobulin domain" refers to a polypeptide consisting of a spherical region of an antibody chain (e.g., a chain of common 4-chain antibodies or chains of heavy chain antibodies) or essentially such spherical regions. The immunoglobulin domain is characterized in that it retains the immunoglobulin folding properties of the antibody molecule and consists of approximately seven antiparallel beta stranded two-layer sandwiches arranged in two beta sheets arbitrarily stabilized by conserved disulfide bonds . An immunoglobulin domain comprises (a) variable domain (s), ie one or more immunoglobulin variable domains.

As used herein, an "immunoglobulin variable domain" is intended to include both "framework region 1" or "FR1"; "Framework Area 2" or "FR2 "; "Framework Area 3" or "FR3 "; And four "framework regions" referred to as "framework regions 4" or "FR4 ",respectively; The framework region is interfered by three "Complementarity Determining Regions" or "CDRs ", CDRs are known in the art and hereinafter as" Complementary Determining Region 1 "or" CDR1 "; "Complementarity determining region 2" or "CDR2 "; And "complementarity determining region 3" or "CDR3 ", respectively. Therefore, the general structure or sequence of the immunoglobulin variable domain can be represented as follows: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. This is an immunoglobulin variable domain that carries antigen binding sites and provides specificity for the antibody to the antigen. In the present invention, immunoglobulin single variable domains such as VHH and domain antibodies are preferred.

As used herein, "immunoglobulin single variable domain" means an immunoglobulin variable domain that is not paired with an additional variable immunoglobulin domain and can specifically bind to an epitope of an antigen. One example of an immunoglobulin single variable domain in the sense of the present invention is a "domain antibody" such as the immunoglobulin single variable domains VH and VL (VH and VL domains). Another example of an immunoglobulin single variable domain is the "VHH domain" (or simply "VHH") derived from camelid as defined below.

In view of the above definition, it is also possible to use a common four chain antibody (e.g. IgG, IgM, IgA, IgD or IgE molecule known in the art), or a Fab fragment, F (ab ') 2 fragment, disulfide- The antigen binding domain of a Fv fragment, such as an scFv fragment, or a diabody (both known in the art) derived from a common quadruplex antibody, is not commonly considered to be an immunoglobulin single variable domain, The binding to each epitope of an antigen is not normally caused by one (single) immunoglobulin domain, but rather by a pair of (binding) immunoglobulin domains, such as light and heavy variable domains, Lt; RTI ID = 0.0 > VH-VL < / RTI > pair of immunoglobulin domains.

VHH, V _H H domains, VHH antibody fragments, and also known as VHH antibodies "VHH domains" original "heavy chain antibody" (ie, "without a light chain antibody"; Hamers-Casterman C, Atarhouch T, Muyldermans S, Robinson G Immunoglobulin (variable) domain of "Naturally occurring antibodies devoid of light chains"; Nature 363, 446-448 (1993)). "VHH domains" refers to the typical four heavy chain variable domain present in the chain antibodies (herein, "V _H domain" or "VH domain" as referred) and the light chain variable domain (where present in the typical four chain antibodies "V _L Domain "or" VL domain "). The VHH domain can specifically bind to the epitope without additional antigen binding domains (as opposed to the VH or VL domains in a common 4-chain antibody in which the epitope is recognized by the VL domain with the VH domain). The VHH domain is a small, potent and efficient antigen recognition unit formed by a single immunoglobulin domain.

In the context of the invention, VHH domains, VHH, V _H H domains, VHH antibody fragment, VHH antibody, "Nanobody®" and "Nanobody® domain" ( "Nanobody" is a trademark of Ablynx NV (Ghent, Belgium)) is Is an exemplary immunoglobulin single variable domain that is used interchangeably and (which has an FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 structure; does not require a second immunoglobulin variable domain and specifically binds to an epitope) , Which are distinguished from the VH domain by a so-called "hallmark residue ", for example as defined in FIG. 1 of WO 2009/109635.

Amino acid residues of immunoglobulin single variable domains, such as VHH, are described in Riechmann and Muyldermans, J. Immunol. (See "Sequence of proteins of immunological interest", US Public Health Services, NIH Bethesda, MD, Publication No. 91 (1999), applied to the VHH domain of camelid as shown in FIG. 2 of Methods 231, 25-38 ) Are numbered according to the general numbering for the V _H domain provided. According to this numbering,

- FR1 comprises an amino acid residue at position 1-30,

CDR1 comprises an amino acid residue at position 31-35,

- FR2 comprises an amino acid residue at position 36-49,

- CDR2 comprises an amino acid residue at position 50-65,

FR3 comprises an amino acid residue at position 66-94,

- CDR3 comprises an amino acid residue at position 95-102,

- FR4 contains amino acid residues at positions 103-113.

However, as is known in the art for the -V _H and VHH domains, the total number of amino acid residues in each CDR may be variable and may not correspond to the total number of amino acid residues indicated by Kabat numbering (I.e., one or more positions due to Kabat numbering may not be within the actual sequence, or the actual sequence may contain more amino acid residues than the number given by Kabat numbering). This generally means that the Kabat numbering may or may not correspond to the actual numbering of the amino acid residues in the actual sequence.

Selectable methods for amino acid residue numbering of the V _H domain, which may also be applied to the VHH domain in a similar manner, are known in the art. However, in the present specification, claims and drawings, the numbering applied to the VHH domain according to Kabat and described above, unless otherwise indicated, is as follows.

The total number of amino acid residues in the VHH domain is generally in the range of 110 to 120, usually 112 to 115. It should be noted, however, that shorter sequences and longer sequences may also be suitable for the purposes described herein.

Immunoglobulin single variable domains, e. G., VHH and domain antibodies according to preferred embodiments of the present invention have a number of unique structural and functional properties which make them highly advantageous for use as functional antigen-binding molecules in therapeutic regimens. In particular, and without limitation, the VHH domain (which is naturally "designed" to operatively bind to the antigen without being paired with the light chain variable domain) may function as a single relatively small functional antigen binding unit .

Due to its unique properties, immunoglobulin single variable domains as defined herein, such as VHH or VH (or VL), have many important advantages - either alone or as part of a macromolecule polypeptide, for example a bicarotope molecule to provide:

There is no need to provide two distinct domains because only a single domain is required to bind the antigen with high affinity and high selectivity, and these two domains may not be present in the correct spatial form and structure (i.e., , Using specially designed linkers);

- the immunoglobulin single variable domain can be expressed from a single nucleic acid molecule and does not require post-translational modification (such as glycosylation);

Immunoglobulin single variable domains can be readily manipulated in multispecific formats (described in detail herein);

The immunoglobulin single variable domain has high specificity and affinity for the target, low specific toxicity and can be administered by alternative routes other than injection or injection;

- Immunoglobulin single variable domains are highly stable to heat, pH, proteases and other dissociation or conditions so that they can be prepared, stored or transported without the use of a cooling device;

- Immunoglobulin single variable domains are easy to manufacture and relatively inexpensive on a small and commercial scale. For example, an immunoglobulin single variable domain may be produced using microbial fermentation (e.g., as described in detail below), and it may be necessary to use a mammalian expression system, such as, for example, No;

Immunoglobulin single variable domains are relatively small (approximately 15 kDa, or 10-fold smaller than normal IgG) compared to conventional four-chain antibodies and their antigen-binding fragments, and thus can be used for tissue (including, but not limited to, solid tumors ≪ / RTI > and other dense tissues) and can be administered at higher doses than conventional 4-chain antibodies and their antigen binding fragments;

- VHH has a so-called "cavity binding property" specific (due to their extended CDR3 loops compared to the VH domain from a 4 chain antibody, in particular), and thus the general 4-chain antibody and its antigen- Accessible targets and epitopes;

- (like the antigen binding domain derived from the mouse described in Ward et al., Nature 341: 544-546 (1989)). VHH has a particular advantage of being highly soluble, stable and free of aggregation tendency.

The immunoglobulin single variable domains of the present invention are not limited to the particular biological source or specific method of preparation for which they are obtained. For example, VHH can be obtained by including the following steps:

(1) isolating the VHH domain of a naturally occurring heavy chain antibody; Screening libraries containing heavy chain antibodies or VHH to isolate VHH from them;

(2) expressing a nucleic acid molecule encoding a VHH having a naturally occurring sequence;

(3) optionally, after affinity maturation, expresses a nucleic acid encoding a humanized VHH (as described herein) or a humanized VHH having a naturally occurring sequence;

(4) “camelizing” (as described below) or such camelized domains of immunoglobulin single variable heavy domains of naturally occurring antibodies of animal species, in particular mammalian species, such as humans; Expresses a nucleic acid molecule encoding;

(5) “camelize” the VH or express a nucleic acid molecule encoding such a camelized VH;

(6) using a method of synthetically or semi-synthetically preparing a protein, polypeptide, or other amino acid sequence;

(7) preparing a nucleic acid molecule encoding the VHH domain using nucleic acid synthesis technology, and then expressing the thus obtained nucleic acid;

(8) performing and / or performing other methods to increase affinity maturation, mutation (e. G., Random mutation or site-specific mutation) and / or affinity and / or specificity of VHH for heavy chain antibodies or VHH;

(9) Combining or selecting previous steps.

Suitable methods and techniques for performing the above steps are well known in the art and will be apparent to those skilled in the art. For example, methods for obtaining a VHH domain that binds to a specific antigen or epitope are described in WO2006 / 040153 and WO2006 / 122786.

According to a particular embodiment, the immunoglobulin single variable domain of the invention or the immunoglobulin single variable domain present in the polypeptide of the invention essentially corresponds to the amino acid sequence of the naturally occurring VHH domain, but the amino acid sequence of the naturally occurring VHH sequence Quot; or "sequence-optimized" (optionally with affinity-specificity) by replacing one or more amino acid residues in the sequence with one or more amino acid residues occurring at the corresponding position (s) in the variable heavy domain of a common 4-chain antibody derived from a human. Lt; / RTI > amino acid sequence). This can be done by methods known in the art which can be generally used by those skilled in the art.

The humanized VHH domain may contain one or more entire human framework region sequences, and in even more specific embodiments, a human frame derived from human germ cell Vh3 sequences DP-29, DP-47, DP-51 or portions thereof It may contain a work region sequence or is highly homologous to it and may optionally be combined with a JH sequence such as JH5. Thus, the humanization protocol involves replacing any VHH residues alone or in combination with corresponding framework 1, 2 and 3 (FR1, FR2 and FR3) residues of germ cell VH genes such as DP 47 , DP 29 and DP 51. can do. Suitable framework regions (FRs) of the immunoglobulin single variable domains of the present invention may be selected, for example, from those disclosed in WO 2006/004678 and may specifically include the so-called "KERE" and "GLEW" classes. . For example, an immunoglobulin single variable domain having amino acid sequence GLEW at approximately 44-47 positions and its individual humanized counterpart. Humanized VHH domains may contain one or more entire human framework region sequences.

For example, the humanized substitution for 103 P, R, S-group and / or VHH belonging to the GLEW- group (defined below) is 108Q to 108L. Methods for humanizing immunoglobulin single variable domains are known in the art.

Binding immunoglobulin single variable domains with improved properties, such as enhanced affinity or reduced immunogenicity, in view of therapeutic applications, can be prepared by techniques known in the art, such as affinity maturation (e.g., Or from naturally occurring immunoglobulin sequences), CDR grafting, humanization, combinations of fragments derived from other immunoglobulin sequences, PCR assays using overlapping primers, and similar techniques for manipulating immunoglobulin sequences well known to those skilled in the art; Or any suitable combination of those described above, also referred to herein as "sequence optimization ". For example, reference may be had to the standard handbook as well as the detailed description and examples.

Where appropriate, a binding molecule with increased affinity can be obtained by affinity maturation of another binding molecule, and the latter is a "mosquito" binding molecule with respect to affinity-maturation molecules.

Methods for obtaining VHH binding to specific antigens or epitopes have already been described, for example, in WO2006 / 040153 and WO2006 / 122786. Also, as described in detail therein, the VHH domain derived from camelid is originally derived from one or more amino acid residues occurring at corresponding positions within the human common 4-chain antibody VH domain, in the original VHH sequence, Optimization "herein refers to a sequence or sequence that provides VHH with improved properties such as the elimination of potential post-translational modification sites in addition to humanization, by " humanized" Which may include further denaturation of the sequence by mutation). The humanized VHH domain may contain one or more entire human framework region sequences and in more particular embodiments may be derived from DP-29, DP-47, DP-51, or a portion thereof, optionally in combination with a JH sequence such as JH5 And may contain the derived human framework region sequence.

Domain antibodies, also known as "Dab" and "dAbs" (the terms "Domain Antibodies" and "dAbs" are used as trademarks of the GlaxoSmithKline group), are described, for example, in Ward, ES, et al .: "Binding activities of a repertoire of single immunoglobulin variable domains secreted from Escherichia coli "; Nature 341: 544-546 (1989); Holt, L.J. et al .: "Domain antibodies: proteins for therapy "; TRENDS in Biotechnology 21 (11): 484-490 (2003); And WO2003 / 002609.

Domain antibody corresponds essentially to the VH or VL domain of a non-camelid mammalian antibody, particularly a human 4-chain antibody. In order to bind to an epitope without being paired as a single antigen binding domain, i. E., With each of the VL or VH domains, a specific selection for this antigen binding property, e. G., By using a single human VH or VL domain sequence library, need.

Domain antibodies have a molecular weight of about 13 to about 16 kDa, such as VHH, and do not require humanization for human therapeutic use, for example, if they are derived from whole human sequences. It is also well expressed in prokaryotic expression systems, such as in the case of the VHH domain, and provides a significant reduction in overall manufacturing costs.

It will also be apparent to those skilled in the art that one or more of the above CDRs can be "grafted " to other" scaffolds ", such as, but not limited to, human scaffolds or non-immunoglobulin scaffolds . Suitable scaffolds and techniques for such CDR transplantation are well known in the art.

The terms "epitope" and "antigenic determinant ", which may be used interchangeably, refer to antigen-binding molecules such as conventional antibodies or polypeptides of the invention, more specifically polypeptides such as those recognized by the antigen- Refers to a portion of a macromolecule. Since the epitope defines the minimal binding site for immunoglobulin, it represents a target of immunoglobulin specificity.

Affinity and / or specificity "polypeptides (e. G., &Quot; affinity ", " affinity " Immunoglobulin, an antibody, an immunoglobulin single variable domain of the invention or a generally antigen-binding molecule or fragment thereof) is referred to as being "against" or "opposing" to the epitope, antigen or protein, "Binding" molecule to an antigen or protein. In this specification, the Dll4-binding component may also be referred to as "Dll4-neutralization".

In general, the term "specificity " refers to the number of different classes of antigens or epitopes that a particular antigen-binding molecule or antigen-binding protein (e.g., an immunoglobulin single variable domain of the invention) molecule can bind. The specificity of an antigen-binding molecule can be determined based on its affinity and / or binding activity. The affinity, expressed as the equilibrium constant (KD) for the separation of antigen and antigen-binding protein, is a measure of the binding force between the epitope and the antigen-binding site on the antigen-binding protein: the lower the KD value, the more the epitope and antigen- (Optionally, affinity can also be expressed as an affinity constant (KA) which is also 1 / KD). As will be apparent to those skilled in the art (based on, for example, the detailed description herein), affinity may be measured in a manner known per se according to the specific antigen of interest. Binding activity is a measure of the binding force between an antigen-binding molecule (e. G., An immunoglobulin, an antibody, an immunoglobulin single variable domain) or a polypeptide containing it and a suitable antigen. Binding activity is related to both the affinity between the epitope and the antigen binding site thereof on the antigen-binding molecule and the number of suitable binding sites present on the antigen-binding molecule.

The portion of the antigen-binding molecule that recognizes the epitope is called paratope.

Unless otherwise indicated, the term "Dll4-binding molecule" or "Ang2-binding molecule" refers to an anti-Dll4 or anti-Ang2 antibody, an anti-Dll4 antibody or an anti-Ang2 antibody fragment, as described herein. -Dll4 antibody-like molecule "or" anti-Ang2 antibody-like molecule "and conjugates with any of these. Antibodies include, but are not limited to, monoclonal antibodies and chimerized monoclonal antibodies. The term "antibody" includes not only complete immunoglobulins, such as monoclonal antibodies produced by recombinant expression in a host cell, but also antibody fragments, or so-called "SMIP" (as described, for example, in WO 2002/056910). "Antibody-like molecules" including single-chain antibodies and linear antibodies called "Small Modular Immunopharmaceuticals"); Antibody-like molecules comprise immunoglobulin single variable domains as defined herein. Another example of an antibody-like molecule is an immunoglobulin superfamily antibody (IgSF) or CDR-grafted molecule.

"Ang2-binding molecules" or "Dll4-binding molecules" refer to monovalent or multivalent binding molecules (ie, more than one epitope), as well as monovalent target-binding molecules (ie, molecules that bind to one epitope of each target), respectively. Refers to all binding molecules that bind to, for example, a "biparatopic" molecule as defined below. Ang2 (or Dll4) -binding molecules containing more than one Ang2 (or Dll4) -binding immunoglobulin single variable domain are also referred to as "formatted" binding molecules, which are immunoglobulin single variable within the target-binding component. Moieties having linker and / or effector action in addition to the domain, such as half-life-extending residues such as albumin-binding immunoglobulin single variable domains, and / or serum albumin Attachment polymers such as PEG and / or fusion partners.

The term "biparatopic Ang2 (or Dll4) -binding molecule" or "biparatopic immunoglobulin single variable domain" as used herein refers to a first immunoglobulin single variable domain and a second immunoglobulin single variable domain as defined herein. Including binding molecules, wherein two molecules bind to two non-overlapping epitopes of each antigen. This biparatopic binding molecule consists of an immunoglobulin single variable domain with different specificities for epitopes. Some of the antigen-binding molecules that recognize epitopes (eg, antibodies or immunoglobulin single variable domains of the invention) are paratophrad.

The formatted binding molecule may also comprise two identical immunoglobulin single variable domains, although less preferred, or two different immunoglobulin single variable domains that recognize the same or overlapping epitopes or their respective antigens. . In this case, two immunoglobulin single variable domains with respect to VEGF may bind to the same or overlapping epitopes of each of the two monomers forming the VEGF dimer.

Typically, the binding molecules of the present invention are 10E-5 to 10E-14 moles / liter (M) or less, preferably 10E-7 to 10E-14 moles / liter (M) or less, more preferably 10E-8 to 10E- Dissociation constant (K _D ) of 14 mol / liter, and even more preferably 10E-11 to 10E-13 (measured with Biacore or Kinexa assay), and / or at least 10E7 ME-1, preferably at least 10E8 ME- 1, more preferably with a binding constant K _A of at least 10E9 ME-1, such as at least 10E11 ME-1. Any K _D value in excess of 10E-4 M is generally considered to represent non-specific binding. Preferably, the polypeptides of the invention bind the desired antigen, ie VEGF or Dll4, with a K _D of less than 500 nM, preferably less than 200 nM, more preferably less than 10 nM, such as less than 500 pM. Specific binding of an antigen-binding protein to an antigen or epitope can be determined, for example, using the assays described herein, Scatchard analysis and / or competitive binding assays such as the radioimmunoassay (RIA), enzyme immunoassay ) And sandwich competition assays, and various variants thereof known per se to the art.

Amino acid residues have been represented according to standard 3-letter or 1-letter amino acid codes, which are generally known and agreed in the art. When comparing two amino acid sequences, the term "amino acid difference" means the addition, deletion or substitution of the amino acid of the designated number at the position of the reference sequence compared to the second sequence. In the case of substitution, such substitution is preferably a conservative substitution of amino acids, which means that the amino acid residues have a similar chemical structure and are substituted with another amino acid residue that has little or no effect on the function, activity or other biological properties of the polypeptide It means to be replaced. Conservative substitutions of such amino acids are well known in the art, for example, in WO 98/49185, conservative substitutions of amino acids are preferably such that one amino acid of the following groups (i)-(iii) is Substitutions substituted with amino acid residues: (i) small aliphatic, nonpolar, or slightly polar residues: Ala, Ser, Thr, Pro, and Gly; (Ii) polar, negatively charged residues and their (uncharged) amides: Asp, Asn, Glu and Gln; (Iii) polar, positive charge residues: His, Arg and Lys; (Iv) macro aliphatic, nonpolar residues: Met, Leu, Ile, Val and Cys; And (v) aromatic residues: Phe, Tyr and Trp. Particularly preferred conservative amino acid substitutions are as follows: Ala to Gly or Ser; Arg to Lys; Asn with Gln or His; Asp to Glu; Cys to Ser; Gln as Asn; Glu as Asp; Gly with Ala or Pro; His as Asn or Gln; Ile to Leu or Val; Leu as Ile or Val; Lys to Arg, Gln or Glu; Met to Leu, Tyr or Ile; Phe to Met, Leu or Tyr; Ser to Thr; Thr to Ser; Trp with Tyr; Tyr to Trp or Phe; Replace Val with Ile or Leu.

A polypeptide or nucleic acid molecule may be, for example, compared to the original biological source and / or reaction medium or culture medium from which it is obtained, other proteins / polypeptides, other nucleic acids, other biological components, or bound thereto in the source or medium, or When separated from at least one other component or at least one contaminant, impurity or minor component, such as a macromolecule, it is considered to be "essentially separated (in)." In particular, the polypeptide or nucleic acid molecule is considered to be "essentially separated" when purified to at least 2-, especially at least 10-fold, more particularly at least 100-fold, and even 1000-fold or more. Polypeptides or nucleic acid molecules present in “essentially isolated form” are preferably homogeneous when judged using suitable chromatography techniques such as polyacrylamide gel electrophoresis.

"Sequence identity" between two Dll4-binding molecule sequences or two Ang2-binding molecule sequences refers to the percentage of amino acids that are identical between the sequences. This can be calculated or determined as described in paragraphs f) of pages 49 and 50 of WO 2008/020079. "Sequence similarity" means the percentage of amino acids that are identical or conservatively substituted.

Alternative methods of amino acid residue numbering of the V _H domain, which can be applied in a similar manner to the VHH domain, are known in the art. However, unless otherwise indicated, the description, claims and figures of the present invention followed numbering according to Kabat, applied to the VHH domain as described above.

“Affinity-matured” Dll4-binding molecules or Ang2-binding molecules, particularly VHH or domain antibodies, comprise one or more alterations in one or more CDRs, which, in comparison to the respective parental Dll4-binding molecules or Ang2-binding molecules, Or improve affinity for Ang2. The affinity-matured Dll4-binding molecules or Ang2-binding molecules of the present invention are known in the art, for example Marks et al., 1992, Biotechnology 10: 779-783, or Barbas, et al., 1994 , Proc. Nat. Acad. Sci. USA 91: 3809-3813; Shier et al., 1995, Gene 169: 147-155; Yelton et al., 1995, Immunol. 155: 1994-2004; Jackson et al., 1995, J. Immunol. 154 (7): 3310-9; And Hawkins et al., 1992, J. Mol. Biol. 226 (3): 889 896; KS Johnson and RE Hawkins, "Affinity maturation of antibodies using phage display ", Oxford University Press 1996.

In the present invention, "amino acid sequence of SEQ ID NO: x" means an amino acid sequence which is 100% identical to the sequence shown in each SEQ ID NO: x unless otherwise stated;

a) an amino acid sequence having at least 80% amino acid identity with the sequence shown in each SEQ ID NO: x;

b) an amino acid sequence having 3, 2, or 1 amino acid difference from the sequence shown in each SEQ ID NO: x.

The terms "cancer" and "cancerous" refer to or describe physiological conditions in mammals that are typically characterized by uncontrolled cell growth / proliferation. Non-limiting examples of cancer that can be treated with the bispecific binding molecules of the present invention include carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More specific examples of such cancers proposed in US 2008/0014196 that may be treated with Dll4 antagonists include squamous cell cancer, small-cell lung cancer, and non-small cell lung cancer. small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer (pancreatic cancer), glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer (colon cancer), colorectal cancer, endometrial carcinoma or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer (prostate cancer), vulval cancer, thyroid cancer, liver cancer Hepatic carcinoma, gastric cancer, melanoma, and various types of head and neck cancers. The dysregulation of angiogenesis can give rise to many disorders that can be treated by the compositions and methods of the present invention. These disorders include both non-neoplastic and neoplastic conditions. Tumors include, but are not limited to those described above.

Non-limiting examples of non-tumor disorders proposed to be treated with Dll4 antagonists in US 2008/0014196 include unwanted or abnormal hypertrophy, arthritis, rheumatoid arthritis (RA), psoriasis ), Psoriatic plaque, sarcoidosis, atherosclerosis, atherosclerotic plaque, diabetic and other retinopathy of prematurity Proliferative retinopathy, retrolental fibroplasia, neovascular glaucoma, age-related macular degeneration, diabetic macular edema, corneal angiogenesis neovascularization, corneal graft neovascularization, corneal graft rejection, retinal / choroidal neovascularization, anterior angle vessel Neovascularization of the angle (rubeosis), ocular neovascular disease, vascular retenosis, arteriovenous malformations (AVM), meningioma, hemangioma (hemangioma), angiofibroma, thyroid hyperplasia (including thyroid hyperplasias, Graves's disease), cornea and other tissue grafts, chronic inflammation, pneumonia, acute lung injury / ARDS, sepsis, primary Primary pulmonary hypertension, malignant pulmonary effusion, cerebral edema (such as associated with acute stroke / closed head injury / trauma), synovial inflammation ), Pannus formation in RA, myositis ossificans, hypertropic bone formation, osteoarthritis (OA), refractory ascites, polycystic ovarian disease) Endometriosis (endometriosis), 3 car spacing of fluid diseases (3 ^rd spacing of fluid diseases; Chronic infections such as pancreatitis, compartment syndrome, burns, intestinal disorders, uterine fibroids, premature labor, IBD (Crohn's disease and ulcerative colitis), kidney allograft rejection allograft rejection, inflammatory bowel disease, nephrotic syndrome, unwanted or abnormal tissue weight gain (not cancer), hemophilic joint, hypertrophic scar, hair growth inhibition , Osier-Weber syndrome, pyogenic granuloma, retrolental fibroplasias, scleroderma, trachoma, vascular adhesion, synovitis (synovitis) ), Dermatitis, preeclampsia, ascites, pericardial effusion (such as that associated with carditis), and pleural effusion.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the present invention relates to a bispecific binding molecule comprising at least one Dll4 binding component and at least one Ang2 binding component.

In a preferred embodiment, the present invention provides a bispecificity comprising at least one Dll4 binding component and at least one Ang2 binding component further comprising at least one other binding component, preferably serum albumin binding component (serum albumin binding molecule). It relates to binding molecules.

In a preferred embodiment, the serum albumin binding component of the binding molecule of the invention is a polypeptide containing an isolated immunoglobulin single variable domain or one or more of the above immunoglobulin single variable domains, wherein said immunoglobulin single variable domain is four A framework region and three complementarity determining regions CDR1, CDR2 and CDR3, respectively, wherein said CDR3 has an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 522, 525, 528, 531, 534, 537, or 540.

More preferably, the at least one immunoglobulin single variable domain of the serum albumin binding component contains:

a. A CDR3 having an amino acid sequence selected from the amino acid sequences of the first group shown in SEQ ID NOs: 522, 525, 528, 531, 534, 537, or 540;

b. SEQ ID NOs: 520, 523, 526; CDR1 having an amino acid sequence selected from the amino acid sequences of the second group shown in 529, 532, 535, or 538;

c. A CDR2 having an amino acid sequence selected from the amino acid sequences of the second group shown in SEQ ID NOs: 521, 524, 527, 530, 533, 536, or 539.

In a more preferred embodiment, the at least one immunoglobulin single variable domain of the serum albumin binding component has a amino acid sequence as shown in VHH, preferably SEQ ID NO: 98 or 519.

According to a preferred embodiment, the Dll4 binding component and the Ang2 binding component each comprise at least one Dll4 binding immunoglobulin single variable domain and at least one Ang2 binding immunoglobulin single variable domain.

In a preferred aspect, the Dll4 binding component and the Ang2 binding component each comprise at least one Ang2 binding immunoglobulin single variable domain and at least one Dll4 binding immunoglobulin single variable domain, wherein each immunoglobulin single variable domain is 4 Three frame regions and three complementarity determining regions CDR1, CDR2 and CDR3, respectively.

Thus, the anti-Dll4 and / or anti-Ang2 components contained in the bispecific binding molecules of the present invention may comprise two (or more) anti-Dll4 (or anti-Ang2, each) immunoglobulin single variable domains. And wherein the immunoglobulin single variable domain is directed against different epitopes within the Dll4 (or Ang2) target. Thus, two immunoglobulin single variable domains in bispecific binding molecules have different antigen specificities and thus different CDR sequences.

These bivalent binding molecules are each "biparatope single domain antibody construct" (immunoglobulin single variable domain) since two immunoglobulin single variable domains will contain two different paratopes. Or consist essentially of a single domain antibody), or "biparatopeic VHH constructs" (when an immunoglobulin single variable domain consists or consists essentially of VHH).

In the bispecific binding molecule of the present invention, one or both binding molecules may be divalent; For example, the Ang2-binding component may be biparatope and the Dll4-binding component may be one immunoglobulin single variable domain, or the Ang2-binding component is one immunoglobulin single variable domain and the Dll4-binding component is bipara It may be topping.

In the bispecific binding molecule of the present invention, it is preferably an Ang2 binding component containing a bivalent Ang2 binding immunoglobulin single variable domain, for example a biparatope VHH.

The Dll4-binding component comprises at least one variable domain having four framework regions and three complementarity determining regions CDR1, CDR2, and CDR3, respectively, wherein CDR3 has an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NO: :

a) SEQ ID NOs: 1 to 166 and 458,

b) SEQ ID NOs: 333 to 353, or

c) SEQ ID NOs: 375 to 395.

The amino acid sequence a) selected from the first group of SEQ ID NOs: 1 to 166 and 458 is contained within the corresponding amino acid sequence selected from the second group sequence described in Table 5 and SEQ ID NOs: 167 to 332 and 459 as partial sequences.

The amino acid sequence b) selected from the first group of SEQ ID NOs: 333 to 353 is contained within the corresponding sequence selected from the second group sequence set forth in Table 16-A and SEQ ID NOs: 354 to 374 as partial sequences.

The amino acid sequence c) selected from the first group of SEQ ID NOs: 375 to 395 is contained within the corresponding sequence selected from the second group sequence set forth in Table 16-B and SEQ ID NOs: 396 to 416 as partial sequences.

In a second aspect, the Dll4-binding component is a polypeptide containing an isolated immunoglobulin single variable domain or one or more immunoglobulin single variable domains, wherein the immunoglobulin single variable domain is comprised of four framework regions and three complementarity determining regions Each of CDR1, CDR2 and CDR3, CDR3 having an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NO:

a) SEQ ID NOs: 1 to 166 and 458,

b) SEQ ID NOs: 333 to 353, or

c) SEQ ID NOs: 375 to 395.

In another aspect, the immunoglobulin single variable domain of the Dll4-binding component is

a) CDR3 having an amino acid sequence selected from the first group of amino acid sequences set forth in SEQ ID NOs: 1-166 and 458;

b) CDR1 and CDR2 having amino acid sequences contained within a sequence selected from the second group amino acid sequences set forth in SEQ ID NOs: 167-332 and 459, as shown in Table 5, wherein SEQ ID NO: 1 SEQ ID NO: x of the first group in 166 corresponds to SEQ ID NO: y of the second group in that y = x + 166.

In another aspect, an immunoglobulin single variable domain is

a) a CDR3 having an amino acid sequence selected from the first group of amino acid sequences set forth in SEQ ID NOs: 333 to 353;

b) CDR1 and CDR2 having amino acid sequences contained within a sequence selected from the second group sequence as set forth in SEQ ID NOs: 354 to 374, as indicated in Table 16-A, wherein SEQ ID NO: x corresponds to SEQ ID NO: y of the second group in that y = x + 21.

In another aspect, an immunoglobulin single variable domain is

a) a CDR3 having an amino acid sequence selected from the first group of amino acid sequences set forth in SEQ ID NOs: 375 to 395;

b) CDR1 and CDR2 having amino acid sequences contained within a sequence selected from the second group sequence set forth in SEQ ID NOs: 396-416 as partial sequences, as shown in Table 16-B, wherein the sequence of the first group Number: x corresponds to SEQ ID NO: y of the second group in that y = x + 21.

In a preferred embodiment, the immunoglobulin single variable domain is VHH.

In another aspect, the VHH has an amino acid sequence selected from amino acids sequences set forth in Table 5 and SEQ ID NOs: 167-332 and 459.

The Ang2-binding component comprises at least one variable domain having four framework regions and three complementarity determining regions CDR1, CDR2 and CDR3, respectively, wherein CDR3 is SEQ ID NOs: 491, 494, 497, 500, 503, And has an amino acid sequence selected from the amino acid sequences set forth in 506, 509, 512, 515, or 518.

In a second aspect, the Ang2-binding component is a polypeptide containing an isolated immunoglobulin single variable domain or one or more immunoglobulin single variable domains, wherein the immunoglobulin single variable domain is comprised of four framework regions and three complementarity determining regions CDR1, CDR2 and CDR3, respectively, wherein CDR3 has an amino acid sequence selected from amino acid sequences set forth in SEQ ID NOs: 491, 494, 497, 500, 503, 506, 509, 512, 515, or 518.

In another aspect, the immunoglobulin single variable domain of the Ang2-binding component contains:

a. CDR3 having an amino acid sequence selected from first group amino acid sequences set forth in SEQ ID NOs: 491, 494, 497, 500, 503, 506, 509, 512, 515, or 518 (see also Table 36);

b. As indicated in Table 22-A or 28, the second group amino acid sequence set forth in SEQ ID NO: 489, 492, 495, 498, 501, 504, 507, 510, 513, or 516 (see also Table 36) as partial sequence CDR1 having an amino acid sequence contained within a sequence selected from;

c. As indicated in Table 22-A or 28, the second group amino acid sequence set forth in SEQ ID NO: 490, 493, 496, 499, 502, 505, 508, 511, 514, or 517 (see also Table 36) as partial sequence CDR2 having an amino acid sequence contained within a sequence selected from.

Preferably, the immunoglobulin single variable domain of the Ang2-binding component is VHH, preferably an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 479, 480, 481, 482, 483, 484, 485, 486, 487, or 488. Has

In another preferred embodiment, the immunoglobulin single variable domain of the Ang2-binding component is obtained by affinity maturation or humanization of the immunoglobulin single variable domain as described herein.

Likewise, the present invention also relates to VHH obtained by affinity maturation or humanization of the VHH of the Ang2-binding component described herein.

Accordingly, the present invention also relates to Ang2-binding VHH having an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 479, 480, 481, 482, 483, 484, 485, 486, 487, or 488.

In therapeutic applications, Dll4- and / or Ang2-binding components having improved properties, such as improved affinity or reduced immunogenicity, may be derived from the individual Dll4- or Ang2-binding components of the present invention (eg, Affinity maturation (starting from synthetic, random or naturally occurring immunoglobulin sequences), CDR grafting, humanization, combinations of fragments derived from different immunoglobulin sequences, PCR assemblies using overlapping primers, and those skilled in the art Analogous techniques for manipulating immunoglobulin sequences known to humans; Or by any suitable combination of these. For example, reference may be made to standard handbooks as well as detailed descriptions and examples.

Preferably, the Dll4-binding component of the present invention with increased affinity is obtained by the affinity maturation of another Dll4-binding component, with the latter representing the "parent" Dll4-binding component. . The same is true for the Ang2-binding component.

Therefore, in another preferred embodiment, the Dll4- or Ang2-binding molecule of the invention is an immunoglobulin single variable domain obtained by the affinity maturation of the parental immunoglobulin single variable domain as defined above.

In another preferred embodiment, the present invention relates to an immunoglobulin single variable domain obtained by affinity maturation of VHH.

Suitable parent Dll4-binding components for affinity maturation are, for example, VHH described above having the amino acid sequences set forth in SEQ ID NOs: 167-332 and 459.

Suitable parent Ang2-binding components for affinity maturation are, for example, VHH described above having the amino acid sequence set forth in SEQ ID NO: 479, 480, 481, 482, 483, or 484.

Accordingly, the present invention also relates to Ang2-binding molecules obtained by affinity maturation and / or sequence optimization of VHH as defined above, for example the amino acid sequences set forth in SEQ ID NOs: 482, 483, 484, 485, 486, 487, 488. It relates to a VHH obtained by sequence optimization of a VHH having a. The “source” amino acid sequence used to generate the latter VHH is described in SEQ ID NOs: 479, 480, or 481. In addition, such amino acid sequences are suitable Ang2-binding components that can be applied to the binding molecules of the present invention.

As described herein, the binding molecules of the present invention preferably comprise at least one serum albumin binding component. Therefore, particularly preferred binding molecules have at least one Dll4-binding component, at least one Ang2-binding component and at least one serum albumin binding component. The order of these three binding components may be any possible order as shown in FIG. 16 or 23, for example, Dll4-, Ang2- or serum albumin binding components may be N-terminal or C-terminal. In particular, "00042", "00045" or "00050" mentioned in the symbol description table of FIG. 16 represents an Ang2-binding component, while "00018" represents a Dll4-binding component and "ALB11" represents a serum albumin binding component. . None of these should be understood as specific sequences, and when used in the context of possible constitution of the binding molecules of the present invention generally refers to Ang2-, Dll4- and serum albumin binding components.

However, it is preferred that the serum albumin binding component be between the Dll4- and Ang2-binding components (or vice versa), at least one Ang2-binding component being an N-terminal, followed by at least one serum albumin binding component, followed by Particular preference is given to the C-terminal being followed by at least one Dll4-binding component. This configuration has been found to be particularly useful.

Therefore, the present invention comprises at least one Dll4-binding component, at least one Ang2-binding component and at least one serum albumin binding component having, in a preferred aspect, an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 460-478. It relates to a binding molecule.

As used herein, the "at least one" binding component (Ang2, Dll4 or serum albumin) is 1, 2, 3, 4, or 5 Ang2-, wherein the binding molecule of the invention is preferably represented by the immunoglobulin single variable domain described herein. , Dll4 and / or serum albumin binding components (ie, entities / units).

In another preferred embodiment, the invention relates to a Dll4 immunoglobulin single variable domain obtained by the affinity maturation of VHH having the amino acid sequence set forth in SEQ ID NO: 197.

In another embodiment, the immunoglobulin single variable domain derived from VHH having the amino acid sequence set forth in SEQ ID NO: 197 is selected from an immunoglobulin single variable domain having the amino acid sequence set forth in SEQ ID NOs: 354-374.

In a preferred embodiment, the immunoglobulin single variable domain is VHH with the amino acid sequence set forth in SEQ ID NO: 358.

In even more preferred embodiments, an immunoglobulin single variable domain is obtained by humanization of VHH having the amino acid sequence set forth in SEQ ID NO: 358.

In another preferred embodiment, the immunoglobulin single variable domain is VHH having the amino acid sequence set forth in SEQ ID NO: 356.

In even more preferred embodiments, the invention relates to an immunoglobulin single variable domain obtained by humanization of VHH having the amino acid sequence set forth in SEQ ID NO: 356.

In another preferred embodiment, the invention relates to an immunoglobulin single variable domain obtained by affinity maturation of VHH having the amino acid sequence set forth in SEQ ID NO: 224.

In another embodiment, the immunoglobulin single variable domain derived from VHH having the amino acid sequence set forth in SEQ ID NO: 224 is selected from an immunoglobulin single variable domain having the amino acid sequence set forth in SEQ ID NOs: 396-416.

In another preferred embodiment, the immunoglobulin single variable domain is a VHH having the amino acid sequence set forth in SEQ ID NO: 402.

In even more preferred embodiments, an immunoglobulin single variable domain is obtained by humanization of VHH having the amino acid sequence set forth in SEQ ID NO: 402.

In another preferred embodiment, the immunoglobulin single variable domain is a VHH having the amino acid sequence set forth in SEQ ID NO: 416.

In even more preferred embodiments, the immunoglobulin single variable domain is obtained by humanization of an immunoglobulin single variable domain having the amino acid sequence set forth in SEQ ID NO: 416.

In another preferred embodiment, the immunoglobulin single variable domain is a VHH having the amino acid sequence set forth in SEQ ID NO: 407.

In even more preferred embodiments, the immunoglobulin single variable domain is obtained by humanization of an immunoglobulin single variable domain having the amino acid sequence set forth in SEQ ID NO: 413.

According to another embodiment, the immunoglobulin single variable domain is a VH domain as defined above.

According to another embodiment, representative of the class of Dll4- and / or Ang2-binding immunoglobulin single variable domains present in the present invention or polypeptides of the invention is "camelized", ie, derived from common 4-chain antibodies. One or more amino acid residues in the amino acid sequence of the naturally occurring variable heavy chain are replaced with one or more amino acid residues occurring at corresponding positions in the VHH domain of the heavy chain antibody to have an amino acid sequence corresponding to the amino acid sequence of the naturally occurring VH domain. This can be done by known methods per se, and is apparent to those skilled in the art, and can also refer to international publication WO 1994/04678. Such camelization may occur preferentially at amino acid positions present at the VH-VL border and at the so-called Camelidae Hallmark residues (see, eg, WO 1994/04678). Such "humanization" and "camelization" methods and preferred framework region sequences consistent with them are described in detail on pages 46 and 98 of WO 2006/040153 and on page 107 of WO 2006/122786.

An immunoglobulin single variable domain or polypeptide containing a Dll4- or Ang2-binding component of the invention, for example, them, may comprise one or more immunoglobulin single variable domains that specifically bind one or more epitopes in each of the Dll4 or Ang2 molecules. It has specificity for Dll4 or Ang2 in that it contains.

Specific binding of each of the Dll4- and / or Ang2-binding components with the antigens Dll4 or Ang2 thereof can be carried out using known and suitable methods, for example assays, Scatchard assays and / or radioimmunoassays described herein. Competitive binding assays such as RIA, enzyme immunoassay (EIA and ELISA), and sandwich competition assays, as well as their different modifications known in the art.

With respect to antigen Dll4, the Dll4 binding component of the invention, for example immunoglobulin single variable domains, is not limited to species. Thus, for the purpose of treating humans, the immunoglobulin single variable domains of the invention or polypeptides containing them preferably bind human Dll4. However, immunoglobulin single variable domains or polypeptides containing them that bind to Dll4 from other mammalian species are also within the scope of the present invention. The immunoglobulin single variable domains of the invention in combination with one species of Dll4 may cross react with one or more other species of Dll4. For example, the immunoglobulin single variable domains of the present invention in combination with human Dll4 are animal models for Dll4 and / or disease of one or more other species of primates, for example monkeys (especially Cynomolgus or Bengal monkeys). (Rhesus)), mice, rats, rabbits, pigs, dogs and, in particular, animal models of diseases and disorders associated with Dll4-mediated effects on angiogenesis (eg, the species and animal models mentioned herein). Exhibit cross reactivity with Dll4 of one or more animal species. The immunoglobulin single variable domains of the present invention exhibiting such cross-reactivity allow the immunoglobulin single variable domain of the present invention to be tested in known disease models such as monkeys, especially cynomolgus monkeys or Bengal monkeys, or mice and rats It is advantageous for research and / or drug development. The same is true for Ang2.

In addition, the Dll4-binding component of the present invention is not limited or defined as the antigenic determinant of the specific domain or Dll4 to which they oppose. Preferably, in view of the cross-reactivity with one or more Dll4 molecules from species other than humans intended to be used as animal models in the development of therapeutic Dll4 antagonists, the Dll4-binding component may be of interest for Dll4 having high identity to human Dll4. Recognize epitopes within a region. For example, in using a mouse model, the immunoglobulin single variable domains of the present invention recognize epitopes located in whole or in part within the EGF-2 domain, indicating high identity between humans and mice. The same is true for Ang2.

Therefore, according to a preferred embodiment, the present invention provides Dll4 selected from the group in which the immunoglobulin single variable domain binds to an epitope contained in whole or in part within the EGF-2 domain corresponding to amino acid residues 252-282 of SEQ ID NO: 417. -Binding components, in particular immunoglobulin single variable domains or polypeptides containing them.

If the polypeptide of the invention is a biparatope molecule as defined herein and it comprises more than one immunoglobulin single variable domain of the invention, the at least one immunoglobulin single variable domain component is an EGF-2 domain as defined above. Binds to epitopes in the stomach.

Preferably, the immunoglobulin single variable domains of the invention have an affinity of less than 10 nM such as less than 500 nM, preferably less than 200 nM, more preferably less than 500 pM with Dll4 and / or Ang2 (as described in Example 5.7). (As measured by surface plasmon resonance analysis).

Preferably, the immunoglobulin single variable domains of the invention range from 10 ⁻⁶ to 10 ⁻¹⁰ moles / liter or less, more preferably 10 ⁻⁸ to 10, as measured in the competition ELISA assay described in Example 5.1. ^It has an IC ₅₀ value in the range of ^-10 moles / liter or less, even more preferably in the range of 10 ^-9 to 10 ^-10 moles / liter or less.

According to a non-limiting preferred embodiment of the invention, the Dll4-binding immunoglobulin single variable domain of the invention or a polypeptide comprising them is 10 to ⁵ to 10 ^-12 moles / liter (M) or less of Dll4, preferably 10 ^{to 7} to 10 ^-12 moles / liter (M) or less, more preferably 10 ^-8 to 10 ^-12 moles / liter (M) dissociation constant (K _D ), and / or at least 10 ⁷ M ^-1 , preferably at least _A binding constant K _A of 10 ⁸ M ⁻¹ , more preferably at least 10 ⁹ M ⁻¹ , such as at least 10 ¹² M ⁻¹ ; And K _D of less than 10 nM, in particular less than 500 nM, preferably less than 200 nM, more preferably less than 500 pM. K _D and K _A values of the immunoglobulin single variable domains of the present invention for Dll4 can be measured. The same is true for Ang2.

In another embodiment, the present invention relates to a Dll4-binding component comprising two or more immunoglobulin single variable domains that bind to antigen Dll4 or Ang2, respectively, in different non-overlapping epitopes. More specifically, such polypeptides of the invention specifically comprise (i) a first immunoglobulin single variable domain that specifically binds to a first epitope of each of Dll4 or Ang2 and (ii) a second epitope of each of Dll4 or Ang2. Consisting essentially of or comprising a second immunoglobulin single variable domain that binds, wherein the first epitope of Dll4 / Ang2 and the second epitope of Dll4 / Ang2 are not the same epitope. In other words, such polypeptides of the invention consist essentially of or comprise two or more immunoglobulin single variable domains for at least two different epitopes present in Dll4 / Ang2, wherein the immunoglobulin single variable domains are simultaneously / Ang2 can be combined with each other in a way that can be combined. In this sense, the polypeptides of the present invention are also "bivalent" or "multivalent" immunoglobulin structures, in particular "multivalent immunoglobulin single variable domain structures, in that the polypeptide comprises at least two binding sites for Dll4 / Ang2. May be considered.

Such Dll4-binding components of the invention comprise (at least) two anti-Dll4 immunoglobulin single variable domains, wherein the two immunoglobulin single variable domains are for different epitopes in the Dll4 molecule. Thus, these two immunoglobulin single variable domains have different antigenic specificities and thus have different CDR sequences. For this reason, a polypeptide of the invention is herein referred to as a "biparatope polypeptide" or "biparatope single domain antibody construct" (if the immunoglobulin single variable domain consists of or consists essentially of a single domain antibody) or "bi Paratope VHH constructs "(if the immunoglobulin single variable domain consists of or consists essentially of VHH), respectively, since the two immunoglobulin single variable domains comprise two different paratopes. This is also true for Ang2 with only minor modifications needed.

According to a specific embodiment of the invention, when the polypeptide of the invention comprises at least two anti-Dll4 immunoglobulin single variable domains, ie three, four or more anti-Dll4 immunoglobulin single variable domains, At least two anti-Dll4 immunoglobulin single variable domains are for different epitopes in the Dll4 molecule, wherein any additional immunoglobulin single variable domains will bind to these two different epitopes and / or other epitopes present in the Dll4 molecule. Can be. This is also true for Ang2 with only minor modifications needed.

According to the invention, two or more immunoglobulin single variable domains may be VH or VHH independently of one another and / or may be another type of immunoglobulin single variable domain, such as a VL domain as defined herein, provided that such immunoglobulin single variable The domain binds to the antigen, ie Dll4 or Ang2, respectively.

Detailed description of the binding components is provided primarily for the Dll4-binding components. However, all of the features and options summarized here for the Dll4-binding component apply equally for the Ang2-binding component with only minor modifications where necessary.

According to a preferred embodiment, the binding molecules present in the bispecific binding molecule (ang2-binding molecule in Ang2-binding component or Dll4-binding molecule in Dll4-binding component or two adjacent Ang2- and Dll4-binding components) It can be linked directly (ie without using a linker) or by a linker. The linker is preferably a linker peptide and is selected such that two different binding molecules can bind to each of the non-overlapping epitopes of the target within one same target molecule or within two different molecules.

In the case of biparatope binding molecules, the choice of linker within the Ang2- or Dll4-binding component depends in particular on the epitope, in particular on the distance between epitopes on the target to which the immunoglobulin single variable domains bind, optionally some limited. After a general experiment of degrees it may become apparent to those skilled in the art based on the description herein.

Two binding molecules (2 VHH or domain antibodies or VHH and domain antibodies) or two binding components may be linked to each other by additional VHH or domain antibodies, respectively (in these binding molecules two or more immunoglobulin single variable domains may be Additional immunoglobulin single variable domains as described above may be linked directly or by a suitable linker). Such additional VHH or domain antibodies can be, for example, VHH or domain antibodies that provide increased half-life. For example, the latter VHH or domain antibody may be capable of binding to (human) serum proteins such as (human) serum albumin or (human) transferrin.

Optionally, two or more immunoglobulin single variable domains that bind each target can be linked in series (directly or by a suitable linker) and additional VHH or domain antibodies (which can provide increased half-life) can be directly or The linker may be linked to one of two or more of the above immunoglobulin sequences.

Suitable linkers have been described herein in connection with specific polypeptides of the invention and may include, but are not limited to, for example, amino acid sequences, wherein the amino acid sequences are preferably at least 9 amino acids, more preferably at least 17 Amino acids, such as about 20-40 amino acids in length. However, the upper limit is not critical and is chosen for simplicity with regard to biopharmaceutical production of such polypeptides.

The linker sequence may be a naturally occurring sequence or an unnaturally occurring sequence. When used for therapeutic purposes, the linker is preferably non-immunogenic in the subject to which the bispecific binding molecule of the invention is administered.

One useful group of linker sequences is the linkers derived from the hinge region of heavy chain antibodies described in WO 1996/34103 and WO 1994/04678.

Another example is a poly-alanine linker sequence, for example Ala-Ala-Ala.

Preferred further examples of linker sequences are Gly / Ser linkers of different lengths, for example (gly _x ser _y ) _z linkers, such as (gly ₄ ser) ₃ , (gly ₄ ser) ₄ , (gly ₄ ser), ( gly ₃ ser), gly ₃ , and (gly ₃ ser ₂ ) ₃ .

Some non-limiting examples of linkers are for example the following linkers described in FIGS. 40 and 48:

GGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGS (35GS; SEQ ID NO: 90);

GGGGSGGGS (9GS; SEQ ID NO: 91);

GGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGS (40GS; SEQ ID NO: 92).

If a bispecific binding molecule is denatured by binding a polymer such as a polyethylene glycol PEG (polyethylene glycol) residue, the linker sequence preferably comprises an amino acid residue such as cysteine or lysine, such as PEGylation in the linker region. This is possible.

Examples of linkers useful for PEGylation include:

GGGGCGGGS ("GS9, C5", SEQ ID NO: 93);

GGGGCGGGGSGGGGSGGGGSGGGGS ("GS25, C5", SEQ ID NO: 94)

GGGSGGGGSGGGGCGGGGSGGGGSGGG ("GS27, C14", SEQ ID NO: 95),

GGGGSGGGGSGGGGCGGGGSGGGGSGGGGSGGGGS ("GS35, C15", SEQ ID NO: 96), and

GGGGCGGGGSGGGGSGGGGSGGGGSGGGGSGGGGS ("GS35, C5", SEQ ID NO: 97).

The linker may also be a poly (ethyl glycol) residue, for example as shown in WO 2004/081026.

In other embodiments, the immunoglobulin single variable domain is optionally linked by other residues (optionally by one or two linkers), such as another polypeptide, which may be an additional immunoglobulin single variable domain as described above in a non-limiting preferred embodiment. Are connected to each other. Such residues may be inert in nature, have a biological effect such as improving the desired properties of the polypeptide, or may provide one or more desirable additional properties to the polypeptide. For example, but not by way of limitation, residues may improve the half-life of a protein or polypeptide and / or reduce its immunogenicity or other desirable properties.

According to a preferred embodiment, the bispecific binding molecules of the invention comprise residues which extend the half-life of the polypeptide of the invention in the serum or other body fluids of the patient, especially when used or intended for use as a therapeutic agent. The term "half-life" is used to reduce the serum concentration of a (denatured) polypeptide by 50% in vivo, for example due to degradation and / or clearance of the polypeptide and / or sequestration by natural mechanisms. It is defined as time.

More specifically, such half-life extending moieties may be covalently linked or fused to an immunoglobulin single variable domain and may comprise an Fc moiety, an albumin moiety, a fragment of an albumin moiety, an albumin binding residue, for example an antialbumin immunoglobulin single variable domain, transferrin Binding residues, such as, but not limited to, antitransferrin immunoglobulin single variable domains, polyoxyalkylene molecules such as polyethylene glycol molecules, albumin binding peptides, or hydroxyethyl starch (HES) derivatives.

In another embodiment, bispecific binding molecules of the invention are directed to a polypeptide of the invention produced comprising a component that binds to an antigen found in blood, such as serum albumin, serum immunoglobulin, thyroxine binding protein, fibrinogen or transferrin. Provides increased half-life in vivo. According to a particularly preferred embodiment, this component is an albumin binding immunoglobulin, in particular an albumin binding immunoglobulin single variable domain, such as an albumin binding VHH domain.

For use in humans, such albumin binding immunoglobulin single variable domains preferably bind to human serum albumin and are preferably humanized albumin binding VHH domains.

Immunoglobulin single variable domains that bind human serum albumin are known in the art and are described, for example, in detail in WO 2006/122786. Particularly useful albumin binding VHHs are ALB 1 and its humanized counterpart ALB 8 (WO 2009/095489). However, other albumin binding VHH domains mentioned in the above patents can also be used.

Particularly useful albumin binding VHH domains are ALB8 consisting of or containing the amino acid sequence set forth in SEQ ID NO: 98 or 519.

According to another embodiment of the invention, the two immunoglobulin single variable domains can be fused to serum albumin molecules, preferably as described in international publications WO 01/79271 and WO03 / 59934 in VHH. For example, as described in WO 2001/79271, fusion proteins can be obtained by general recombinant techniques: DNA molecules encoding serum albumin, or fragments thereof, are DNA encoding bispecific binding molecules. The resulting construct is introduced into plasmids suitable for expression in selected host cells, for example yeast cells, such as Pichia pastoris, or bacterial cells, and then transfected into the fused nucleotide sequence. Incubate under suitable conditions. Useful sequences of HSAs are shown in SEQ ID NO: 99.

According to another embodiment, denaturation (also such denaturation reduces the immunogenicity of the polypeptide) of the polypeptide of the present invention is a suitable pharmacologically acceptable polymer such as straight or branched poly (ethylene glycol) (PEG) Or a derivative thereof (eg, methoxypoly (ethylene glycol) or mPEG). In general, suitable forms of PEGylation, such as PEGylation, used in antibodies and antibody fragments (eg, but not limited to domain antibodies and scFv) can be used; For example, reference may be made to Chapman, Nat. Biotechnol., 54, 531-545 (2002); Veronese and Harris, Adv. Drug Deliv. Rev. 54, 453-456 (2003); Harris and Chess, Nat. Rev. Drug. Discov. 2 (2003); And WO 2004/060965.

Various reagents for PEGylation of polypeptides are commercially available, for example, from Nektar Therapeutics (US), or NOF Corporation (Japan), such as Sunbright® EA Series, SH Series, MA Series, CA Series, and ME. Series such as Sunbright® ME-100MA, Sunbright® ME-200MA, and Sunbright® ME-400MA.

Preferably, site specific PEGylation is used in particular by cysteine residues (see, eg, Yang et al., Protein Engineering 16, 761-770 (2003)). For example, for this purpose PEG is bound to a naturally occurring cysteine residue in a polypeptide of the invention, and the polypeptide of the invention is modified to suitably introduce one or more cysteine residues for PEG binding, or for PEG binding. Amino acid sequences comprising one or more cysteine residues can be fused to polypeptides N- and / or C-terminals of the invention, all of which employ protein manipulation techniques known to those skilled in the art.

Preferably, the PEG in the polypeptide of the invention is more than 5 kDa, for example more than 10 kDa and less than 200 kDa, for example less than 100 kDa; For example, it is used at a molecular weight ranging from 20 kDa to 80 kDa.

With regard to PEGylation, in general, the present invention also preferably discloses that PEGylation (1) increases half-life in vivo; (2) reduce immunogenicity; (3) provide one or more additional advantageous properties known for PEGylation; (4) does not essentially affect the affinity of the polypeptide for its target (e.g., as measured by a suitable assay described in the art, with affinity greater than 50%, more preferably greater than 10%) Does not reduce); And / or (5) in a manner that does not affect other desirable properties of the bispecific binding molecules of the present invention, it should be noted that they include pegylated bispecific binding molecules at one or more amino acid positions. Suitable PEG-groups and methods for binding them specifically or nonspecifically are apparent to those skilled in the art. Various reagents for PEGylation of polypeptides are commercially available, for example, from Nektar Therapeutics (US), or NOF Corporation (Japan), such as Sunbright® EA Series, SH Series, MA Series, CA Series, and ME. Series such as Sunbright® ME-100MA, Sunbright® ME-200MA, and Sunbright® ME-400MA.

According to a particularly preferred embodiment of the invention, the PEGylated polypeptide of the invention comprises one PEG moiety of a linear PEG having a molecular weight of 40 kDa or 60 kDa, wherein the PEG moiety is directed to the polypeptide in the linker region, in particular Position 5 of the GS9-linker peptide shown in SEQ ID NO: 93, position 14 of the GS27-linker peptide shown in SEQ ID NO: 95, or position 15 of the GS35-linker peptide shown in SEQ ID NO: 96, or SEQ ID NO: 97 Binds to position 5 of the 35GS-linker peptide.

The bispecific binding molecules of the present invention may be PEGylated with one of the above PEG reagents, for example "Sunbright® ME-400MA", represented by the formula:

Bispecific binding molecules containing linkers and / or half-life extending functional groups are shown in SEQ ID NOs: 81 and FIG.

According to another embodiment, the immunoglobulin single variable domain is a domain antibody as defined herein.

The immunoglobulin single variable domains present in the bispecific binding molecules of the present invention may be "camelized", ie one or more amino acid residues in the amino acid sequence of a naturally occurring variable heavy chain derived from a common four-chain antibody. It has an amino acid sequence corresponding to the amino acid sequence of a naturally occurring VH domain by replacing one or more amino acid residues occurring at corresponding positions in the VHH domain. This can be done by known methods per se, is apparent to those skilled in the art, and can also refer to international publication WO 94/04678. Such camelization can occur preferentially at amino acid positions present at the VH-VL border and at the so-called Camelidae Hallmark residues (see, eg, WO 94/04678). Such "humanization" and "camelization" methods and preferred framework region sequences consistent with them are described in detail on pages 46 and 98 of WO 2006/040153 and on page 107 of WO 2006/122786.

In the preferred embodiment they have specificity for Ang2 or Dll4 respectively in that they comprise one or more immunoglobulin single variable domains that specifically bind to one or more epitopes in the Ang2 molecule or Dll4 molecule.

Specific binding of the binding component to its antigen Ang2 or Dll4 can be accomplished by, for example, the assays described herein, Scatchard assays and / or competitive binding assays such as radioimmunoassay (RIA), enzyme immunoassay (EIA). And ELISA) and sandwich competition assays, and their variants known per se in the art, can be measured in any suitable manner known per se.

With respect to antigen Ang2 or Dll4, respectively, immunoglobulin single variable domains are not limited in relation to species. Thus, for the purpose of treating humans, the immunoglobulin single variable domain preferably binds to either human Ang2 or human Dll4, respectively. However, immunoglobulin single variable domains or polypeptides containing them that bind to Ang2 or Dll4, respectively, from other mammalian species are also within the scope of the present invention. An immunoglobulin single variable domain combined with one species form of Ang2 or Dll4 may cross react with individual antigens of one or more other species. For example, an immunoglobulin single variable domain that binds to a human antigen is an animal model for individual antigens and / or diseases of one or more other species of primates, for example monkeys (especially Cynomolgus or Rhesus). )), Mice, rats, rabbits, pigs, dogs, and one or more animal species used in animal models (e.g., species and animal models mentioned herein), particularly those that can be modulated by Ang2 inhibition. Cross-reactivity with the antigen. The immunoglobulin single variable domains of the present invention exhibiting such cross-reactivity allow the immunoglobulin single variable domain of the present invention to be tested in known disease models such as monkeys, especially cynomolgus monkeys or Bengal monkeys, or mice and rats It is advantageous for research and / or drug development.

In addition, the binding component is not limited or defined as the antigenic determinant of the specific domain or antigen to which they oppose. Preferably, in the development of therapeutic Ang2 / Dll4 antagonists, in view of the cross-reactivity with one or more antigenic molecules derived from species other than humans intended to be used as animal models, the binding components may be present in individual antigenic regions having a high degree of identity with human antigens. Recognize epitopes. For example, in using a mouse model, the anti-Ang2 immunoglobulin single variable domain contained within the bispecific binding molecule of the invention is located in whole or in part within the EGF-2 domain of Ang2, which exhibits high identity between human and mouse. Recognize epitopes.

Therefore, according to a preferred embodiment, the bispecific binding molecule of the invention is an immunoglobulin single selected from the group that binds to epitopes contained in whole or in part within the EGF-2 domain corresponding to amino acid residues 252-282 of SEQ ID NO: 101. It includes the variable domain Dll4-binding molecule.

In another aspect, the invention relates to a nucleic acid molecule encoding a bispecific binding molecule of the invention. Such nucleic acid molecules will also be referred to herein as "nucleic acids of the present invention" and will also be in the form of genetic constructs as defined herein. The nucleic acid of the present invention may be a genomic DNA, a cDNA, or a synthetic DNA (e. G., A DNA having a codon usage specifically adapted for expression in a desired host cell or host organism). According to one embodiment of the present invention, the nucleic acid of the present invention is a substantially isolated form as defined above.

The nucleic acids of the present invention may also be in the form of a vector such as, for example, a plasmid, cosmid or YAC, may be present in the vector and / or may be part of a vector. The vector may in particular be an expression vector, ie, a vector capable of providing for the expression of bispecific binding molecules in vitro and / or in vivo (ie in a suitable host cell, host organism and / or expression system). Such expression vectors generally comprise at least one nucleic acid of the invention operably linked to one or more suitable regulatory elements, such as a promoter, enhancer, terminator, and the like. These components and their selection in terms of expression of specific sequences in a particular host are common knowledge to those skilled in the art. Specific examples of regulatory elements and other elements useful or necessary for expressing the bispecific binding molecules of the invention, such as promoters, enhancers, terminators, integration factors, selectable markers, leader sequences, reporter genes, For example, in WO 2006/040153 pages 131-133.

Based on the amino acid sequence information of the polypeptide of the present invention provided herein, the nucleic acid of the present invention may be produced or obtained in a manner known per se (for example, automatic DNA synthesis and / or recombinant DNA technology) and / Can be isolated from a suitable natural source.

In another aspect, the present invention relates to a host cell capable of expressing or expressing one or more bispecific binding molecules of the present invention and / or containing a nucleic acid of the present invention. According to a particularly preferred embodiment, the host cell is a bacterial cell; Other useful cells are yeast cells, fungal cells or mammalian cells.

Suitable bacterial cells include Escherichia cells of Gram-negative bacterial strains such as strains of coli , Proteus , and Pseudomonas and strains of Gram-positive bacteria such as strains of Bacillus , Streptomyces , Staphylococcus , and Lactococcus . Suitable fungal cells include cells of Trichoderma , Neurospora and Aspergillus species. Suitable yeast cells are Saccharomyces (eg Saccharomyces cerevisiae ), Schizosaccharomyces (eg Schizosaccharomyces pombe ), Pichia (e.g. Pichia pastoris and Pichia methanolica ), and Hansenula . Lt; / RTI > cells.

Suitable mammalian cells include, for example, CHO cells, BHK cells, HeLa cells, COS cells, and the like. However, amphibious cells, insect cells, plant cells, and any other cells used in the art of heterologous protein expression may also be used.

The present invention further provides a method of preparing the bispecific binding molecule of the present invention, which generally comprises the following steps:

Culturing a host cell comprising a nucleic acid capable of encoding a bispecific binding molecule under conditions capable of expressing the bispecific binding molecule of the invention;

Recovering or isolating the polypeptide expressed by the host cell from the culture; And

Optionally further purification and / or denaturation and / or formulation of the bispecific binding molecules of the invention.

For industrial scale production, preferred host organisms include E. coli , Pichia pastoris , and S. cerevisiae strains which are suitable for large scale expression, production and fermentation, and especially for large scale pharmaceutical expression, production and fermentation.

The selection of a specific expression system depends in part on the requirements for specific post-translational modification, more specifically glycosylation. Production of bispecific binding molecules of the invention, where glycosylation is desired or required, may require the use of an expression host in a mammal having the ability to glycosylate the expressed protein. In this respect, it will be apparent to those skilled in the art that the glycosylation pattern obtained (i. E., The type, number and location of bound residues) will depend on the cell or cell line used for expression.

Bispecific binding molecules of the invention are produced intracellularly (eg, in a cell substrate, periplasm or inclusion body) in cells as set forth above, then isolated from host cells and optionally further purified; They may be produced extracellularly (e. G., In a culture medium in which the host cell has been cultured), then isolated from the culture medium and optionally further purified.

Methods and reagents used in the recombinant production of polypeptides, such as suitable specific expression vectors, transformation or transfection methods, selectable markers, methods of inducing protein expression, culture conditions, and the like, are known in the art. Likewise, techniques for protein isolation and purification useful in the polypeptide preparation methods of the present invention are well known to those skilled in the art.

In a further aspect, the invention provides a CDR3 contained in an anti-Dll4-VHH having an amino acid sequence selected from the sequences set forth in SEQ ID NOs: 1-166 and 458, SEQ ID NOs: 333-353, or SEQ ID NOs: 375-395, respectively. A peptide having an amino acid sequence of and a nucleic acid molecule encoding the same.

Such peptides correspond to CDR3 derived from the VHH of the present invention. These, in particular the nucleic acid molecules encoding them, are CDR grafted to replace CDR3 in immunoglobulin chains, or non-immunoglobulin scaffolds such as protease inhibitors, DNA-binding proteins, cytochrome b562, helix-bundle proteins, disulfide- It is useful to impart target-binding characteristics to these scaffolds upon insertion into crosslinked peptides, lipocalins or anticalins. CDR-grafting methods are well known in the art and are widely used, for example, for humanized antibodies, including transplanting CDRs of rodent antibodies onto Fv frameworks of human antibodies.

In order to obtain an immunoglobulin or non-immunoglobulin scaffold containing the CDR3 of the present invention, DNA encoding such molecules can be isolated by standard methods of molecular biology, such as gene synthesis, oligonucleotide annealing or, for example, Daugherty et al., 1991, Nucleic acid Research, Vol. 19, 9, 2471-2476. Methods for inserting VHH CDR3 into non-immunoglobulin scaffolds are described in Nicaise et al., 2004, Protein Science, 13, 1882-1891.

The invention further relates to products or compositions which contain or comprise at least one bispecific binding molecule of the invention and optionally one or more additional components of the composition known per se, ie according to the intended use of the composition.

For pharmaceutical use, a bispecific binding molecule of the invention or a polypeptide containing the same comprises at least one bispecific binding molecule of the invention and at least one pharmaceutically acceptable carrier, diluent or additive and / or adjuvant, and optionally It may be formulated as a pharmaceutical agent or composition comprising one or more pharmaceutically active additional polypeptides and / or compounds. By way of non-limiting example, such agents are suitable for oral administration, parenteral administration (e.g., intravenous, intramuscular or subcutaneous or intravenous infusion), topical administration, administration by inhalation, skin patches, implants, suppositories, etc. It may be in the form. Such suitable dosage forms, which may be solid, semisolid or liquid depending on the mode of administration, as well as methods and carriers for use in the preparation thereof, will be apparent to those skilled in the art and are further described herein.

Thus, in another aspect, the invention relates to at least one bispecific binding molecule, in particular one immunoglobulin single variable domain of the invention or a polypeptide containing the same, and at least one suitable carrier, diluent or (ie, pharmaceutical use) Suitable) additives, and optionally one or more additional active substances.

The bispecific binding molecules of the invention can be formulated and administered in a suitable manner known in the art: in particular for immunoglobulin single variable domains, reference may be made to, for example, WO 2004/041862, WO 2004/041863, WO 2004/041865, WO 2004/041867 and WO 2008/020079, and standard handbooks such as Remington's Pharmaceutical Sciences, 18 ^th Ed., Mack Publishing Company, USA (1990), Remington, the Science and Practice of Pharmacy, 21 ^th Edition, Lippincott Williams and Wilkins (2005); Or the Handbook of Therapeutic Antibodies (S. Dubel Ed.), Wiley, Weinheim, 2007 (see for example pages 252-255).

For example, the immunoglobulin single variable domains of the invention can be formulated and administered by known methods for conventional antibodies and antibody fragments (including ScFv and diabodies) and other pharmaceutically active proteins. Such formulations and methods of making them are apparent to those skilled in the art and include, for example, parenteral administration (eg, intravenous, intraperitoneal, subcutaneous, intramuscular, intraluminal, intraarterial or intrathecal) or topical ( That is, preparations suitable for transdermal or intradermal) administration.

The preparation for parenteral administration may be, for example, a sterile solution, suspension, dispersion or emulsion, suitable for injection or injection. Suitable carriers or diluents for such preparations are, for example, sterile water and pharmaceutically acceptable aqueous buffers and solutions such as physiological phosphate buffered saline, Ringer's solution, dextrose solution and Hank's solution; Water oil; Glycerol; ethanol; But are not limited to, glycols such as propylene glycol or mineral oils, animal oils and vegetable oils, such as peanut oil, soybean oil, and mixtures of suitable ones. In general, aqueous solutions or suspensions are preferred.

Accordingly, the bispecific binding molecules of the present invention can be administered systemically, for example orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. For oral therapeutic administration, the bispecific binding molecules of the present invention may be formulated with ingestible tablets, buccal tablets, troches, capsules, elixirs, Suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of the Dll4 binding molecules of the invention. The proportions thereof in the compositions and formulations can, of course, be varied and can conveniently be in the form of a given unit dose of from about 2 to about 60 weight percent. The amount of bispecific binding molecules of the invention in such therapeutically useful compositions is such that an effective dosage level can be obtained.

Tablets, pills, capsules and the like may also include binders, additives, disintegrants, lubricants and sweeteners or flavoring agents, which are mentioned on pages 143-144 of WO 08/020079. When the unit dosage form is a capsule, it may contain a liquid carrier such as vegetable oil or polyethylene glycol in addition to the above-mentioned kinds of materials. Various other materials may be present as coatings or to otherwise alter the physical form of the solid unit dosage form. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac, sugar, or the like. Syrups or elixirs may contain the bispecific binding molecules of the present invention, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, flavors such as dyes and cherry flavors or orange flavors. The materials used to make any unit dosage form should, of course, be pharmaceutically acceptable and substantially non-toxic in the amounts used. In addition, bispecific binding molecules of the invention can be combined with sustained release agents and devices.

Preparations and formulations for oral administration may also be presented as enteric coated tablets in which the structure of the present invention can tolerate the gastrointestinal environment and pass the intestines. More generally, formulations and preparations for oral administration may be suitably formulated for delivery to the desired site of the gastrointestinal tract. In addition, suitable suppositories may be used for delivery to the gastrointestinal tract.

Bispecific binding molecules of the invention can also be administered intravenously or intraperitoneally by infusion or injection as described in detail in pages 144-145 of WO2008 / 020079.

For topical administration of the bispecific binding molecules of the invention, it is generally the administration as described in detail on page 145 of WO 2008/020079 in combination with a dermatologically acceptable carrier which may be solid or liquid as a composition or formulation. desirable.

Generally, the concentration of bispecific binding molecules of the present invention in liquid compositions such as lotions is about 0.1-25 wt-%, preferably about 0.5-10 wt-%. The concentration in the solid composition such as semi-solid, or gel or powder is about 0.1-5 wt-%, preferably about 0.5-2.5 wt-%.

The amount of bispecific binding molecule of the invention required for use in therapy depends not only on the particular bispecific binding molecule selected, but also on the route of administration, the nature of the condition being treated and the age and condition of the patient, ultimately at the discretion of the attending physician or clinician. . In addition, the dosage of the bispecific binding molecule of the present invention may vary depending on the target cell, tumor, tissue, graft or organ. Preferred doses may conveniently be provided in a single dose or divided doses administered at appropriate intervals as, for example, 2, 3, 4 or more sub-doses per day. The sub-doses themselves may be further subdivided, for example, by a plurality of separate roughly dispersed doses; Multiple inhalation from the mouth or application of several drops to the eye is an example.

Medication regimens include long-term treatment, and one-day treatment. The term "organ" means a period of at least two weeks, preferably several weeks, months or even years. Those skilled in the art can only use the general experiments provided herein to determine the required modifications of the dosage range. Remington ' s Pharmaceutical Sciences (Martin, E. W., ed. 4), Mack Publishing Co., Easton, Pa. In addition, in the case of complications, the individual physician may adjust the dosage.

According to another embodiment, the invention relates to the use of a bispecific binding molecule of the invention, for example an immunoglobulin single variable domain or a polypeptide containing the same, for example for the following therapeutic purposes:

In particular humans, which may be associated with Dll4-mediated and / or Ang2-related effects on angiogenesis, or which may be prevented, treated or alleviated by modulating the Notch signaling pathway and / or Tie2 signaling pathway with bispecific binding molecules according to the invention. Prevention, treatment and / or alleviation of disorders, diseases or conditions of;

-Administering to the subject in need of such therapy a pharmaceutically active amount of at least one bispecific binding molecule of the invention, for example an immunoglobulin single variable domain, or a pharmaceutical composition containing the same Methods of treatment of patients in need of therapy;

Preparation of a medicament for the prevention, treatment or alleviation of a disorder, disease or condition associated with Dll4-mediated and / or Ang2-mediated effects on angiogenesis;

- the active ingredient of the pharmaceutical composition or medicament used for said purpose.

According to a particular aspect, the disorder, disease or condition is a cancer or cancerous disease as defined herein.

According to another aspect, the disease is an eye disease associated with Dll4-mediated and / or Ang2-mediated effects on angiogenesis, or which can be treated or alleviated by regulating the Notch signaling pathway and / or Tie2 signaling pathway as bispecific binding molecules. to be.

Depending on the cancerous disease to be treated, the bispecific binding molecules of the present invention are themselves or therapeutically inhibiting cancer cells, in particular chemotherapeutic agents such as DNA damaging agents or neovascularization, signal transduction pathways or mitosis checkpoints. It can be used in combination with one or more additional therapeutic agents selected from active compounds.

The additional therapeutic agent may optionally be administered simultaneously as a component of the same pharmaceutical preparation or before or after administration of the bispecific binding molecule.

In certain embodiments, the additional therapeutic agent is EGFR, VEGFR, HER2-neu, Her3, Aurora A, Aurora B, PLK and PI3 kinase, FGFR, PDGFR, Raf, Ras, KSP, PDK1, PTK2, IGFR or IR At least one inhibitor selected from the group consisting of inhibitors of, but is not limited thereto.

Other examples of additional therapeutic agents include inhibitors of CDK, Akt, src / bcr abl, cKit, cMet / HGF, c-Myc, Flt3, HSP90, hedgehog antagonists, JAK / STAT, Mek, mTor, NFkappaB, pro A proteasome, an inhibitor of Rho, an inhibitor of wnt signaling or an inhibitor of the ubiquitination pathway or other inhibitors of the Notch signaling pathway.

Examples of aurora inhibitors include, but are not limited to, PHA-739358, AZD-1152, AT 9283, CYC-116, R-763, VX-680, VX-667, MLN-8045 and PF-3814735.

An example of a PLK inhibitor is GSK-461364.

Examples of raf inhibitors are BAY-73-4506 (also also an inhibitor of VEGFR), PLX 4032, RAF265 (also added VEGFR inhibitor), sorafenib (also added VEGFR inhibitor), and XL 281.

Examples of KSP inhibitors are ispinesib, ARRY-520, AZD-4877, CK-1122697, GSK 246053A, GSK-923295, MK-0731, and SB-743921.

Examples of src and / or bcr-abl inhibitors include dasatinib, AZD-0530, bosutinib, XL 228 (also an inhibitor of IGF-1R), neurotinib (an inhibitor of PDGFR and cKit , Imatinib (also a cKit inhibitor), and NS-187.

An example of a PDK1 inhibitor is BX-517.

An example of a Rho inhibitor is BA-210.

Examples of PI3 kinase inhibitors are PX-866, BEZ-235 (which is also an inhibitor of mTor), XL 418 (which is also an inhibitor of Akt), XL-147, and XL 765 (which are also inhibitors of mTor).

Examples of inhibitors of cMet or HGF include XL-184 (also a inhibitor of VEGFR, cKit, Flt3), PF-2341066, MK-2461, XL-880 (also a VEGFR inhibitor), MGCD-265 (also VEGFR, Ron, Inhibitors of Tie2), SU-11274, PHA-665752, AMG-102, and AV-299.

An example of a c-Myc inhibitor is CX-3543.

Examples of Flt3 inhibitors include AC-220 (also an inhibitor of cKit and PDGFR), KW 2449, lestaurtinib (also an inhibitor of VEGFR, PDGFR, PKC), TG-101348 (also a JAK2 inhibitor), XL-999 (Also inhibitors of cKit, FGFR, PDGFR and VEGFR), sunitinib (also inhibitors of PDGFR, VEGFR and cKit), and tandutinib (also inhibitors of PDGFR and cKit).

Examples of HSP90 inhibitors are tanespimycin, alvespimycin, IPI-504 and CNF 2024.

Examples of JAK / STAT inhibitors are CYT-997 (also interacting with tubulin), TG 101348 (also an inhibitor of Flt3), and XL-019.

Examples of Mek inhibitors are ARRY-142886, PD-325901, AZD-8330 and XL 518.

Examples of mTor inhibitors include temsirolimus, AP-23573 (also acting as a VEGF inhibitor), everolimus (also a VEGF inhibitor), XL-765 (a PI3 kinase inhibitor) and BEZ-235 It is also an inhibitor).

Examples of Akt inhibitors are periopsin, GSK-690693, RX-0201 and triciribine.

Examples of cKit inhibitors include but are not limited to AB-1010, OSI-930 (also acting as a VEGFR inhibitor), AC-220 (which is also an inhibitor of Flt3 and PDGFR), tandouinib (also an inhibitor of Flt3 and PDGFR), axitinib (Also an inhibitor of VEGFR and PDGFR), XL-999 (also an inhibitor of Flt3, PDGFR, VEGFR, FGFR), sunitinib (also an inhibitor of Flt3, PDGFR, VEGFR) and XL- (Also acting as a PDGFR inhibitor), imatinib (also an inhibitor of bcr-abl), nilotinib (also an inhibitor of bcr-abl and PDGFR).

Examples of hedgehog antagonists are IPI-609 and CUR-61414.

Examples of CDK inhibitors include seliciclib, AT-7519, P-276, ZK-CDK (which also inhibits VEGFR2 and PDGFR), PD-332991, R-547, SNS-032, PHA-690509 and AG 024322.

Examples of proteasome inhibitors are bortezomib, carfilzomib, and NPI-0052 (which are also inhibitors of NFkappaB).

An example of an NFkappaB pathway inhibitor is NPI-0052.

An example of a ubiquitination pathway inhibitor is HBX-41108.

In a preferred embodiment, the additional therapeutic agent is an anti-angiogenic agent.

Examples of anti-angiogenic agents are inhibitors of FGFR, PDGFR and VEGFR or ligands of each (e.g., VEGF inhibitor or anti-VEGF antibody bevacizumab) such as pegaptanib, and thalidomide. Formulations include bevacizumab, motesanib, CDP-791, SU-14813, telatinib, KRN-951, ZK-CDK (which is also an inhibitor of CDK), ABT-869, BMS-690514, RAF-265, IMC-KDR, IMC-18F1, IMiDs (immunomodulator), thalidomide derivative CC-4047, lenalidomide, ENMD 0995, IMC-D11, Ki 23057, brivanib, cediranib, XL- 999 (also inhibitor of cKit and Flt3), 1B3, CP 868596, IMC 3G3, R-1530 (also inhibitor of Flt3), sunitinib (also inhibitor of cKit and Flt3), axitinib (inhibitor of cKit ), Lestaurtinib (also an inhibitor of Flt3 and PKC), batalanib, tandutinib (also an inhibitor of Flt3 and cKit), pazopanib, GW 786034, PF-3 37210, IMC-1121B, AVE-0005, AG-13736, E-7080, CHIR 258, sorafenib tosylate (which is also an inhibitor of Raf), RAF-265 (which is also an inhibitor of Raf), vandetanib, CP-547632, OSI-930, AEE-788 (which are also inhibitors of EGFR and Her2), BAY-57-9352 (which are also inhibitors of Raf), BAY-73-4506 (which are also inhibitors of Raf), XL 880 ( is also an inhibitor of cMet), XL647 (also is an inhibitor of EGFR and EphB4), XL 820 (also is an inhibitor of cKit), and nilotinib (also is an inhibitor of cKit and brc-abl) Does not.

Additional therapeutic agents may also be selected from small molecule EGFR inhibitors or EGFR inhibitors which may be anti-EGFR antibodies. Examples of anti-EGFR antibodies include, but are not limited to, Cetuximap, Panitumumap, Matuzumap; An example of a small molecule EGFR inhibitor is zetimidine. An example of another EGFR modulator is the EGF fusion toxin.

Among the EGFR and Her2 inhibitors are lapatinib, gefitinib, erlotinib, cetuximab, trastuzumab, nemotoumuem, zalutumug, vanetanib (also an inhibitor of VEGFR), pertuzumab, (Also an inhibitor of VEGFR), ARRY-333786, IMC-11F8, Zemab, and the like, Are useful in combination with the bispecific binding molecules of the present invention.

Other agents that may be advantageously combined in the therapy with the bispecific binding molecules of the invention include tositumumab and ibritumomab tiuxetan (two radiolabeled anti-CD20 antibodies), Alemtuzumab (anti-CD52 antibody), denosumab (osteocell differentiation factor ligand inhibitor), gallicimab (CD80 antagonist), opatumumab (CD20 inhibitor), zanolimumab (CD4 antagonist), SGN40 (CD40 ligand receptor modulator), rituximab (CD20 inhibitor) or mapatumumab (TRAIL-1 receptor agonist).

Other chemotherapeutic agents that can be used in combination with the bispecific binding molecules of the present invention include hormones, hormone analogs and anti-hormonal agents (eg tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, Nilutamide, bicalutamide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, methoxyprogesterone, octreotide, aroxifene, pasirotide, vapreotide) , Aromatase inhibitors (e.g. anastrozole, letrozole, liarosol, exemestane, atamestane, pomestan), LHRH agonists and antagonists (e.g. goserelin acetate, leuprolide, abarelix, set Lorelix, deslorellin, histrelin, tryptorelin), anti-metabolites such as antifolates such as methotrexate, pemetrexed, pyrimidine analogs, eg Into 5-fluoro-uracil, capecitabine, decimation turbine, Nella Rabin and gemcitabine, Murray, for purine and adenosine analogues, for mercapto purine thioguanine, cladribine and pento statins, among other Lavigne, fludarabine); Antitumor antibiotics such as anthracyclines such as doxorubicin, daunorubicin, epirubicin and dirubicin, mitomycin-C, bleomycin dactinomycin, plicamycin, mitoxantrone, ); Platinum derivatives (e.g., cisplatin, oxaliplatin, carboplatin, robaplatin, satraprapatin); But are not limited to, alkylating agents such as estra mastin, mechlorethamine, melphalan, chlorambucil, piled, dacarbazine, cyclophosphamide, iospamese, hydroxyurea, temozolomide, nitroso urea, Camustine, and rosemary, thiotepa); Antagonists such as antimitotic agents (e.g., vinca alkaloids such as vinblastine, vindesine, vinorelbine, bin flunin and vincristine; and taxanes such as paclitaxel, docetaxel and its formulation, raarotaxel, Tilones such as xyvesperone, patulopyrone, ZK-EPO); Topoisomerase inhibitors (e. G., Epiproteinotics such as etoposide and etophorphos, tenifoside, amsacrine, topotecan, irinotecan) and many chemotherapeutic agents such as aminostatin, But are not limited to, interleukin, interleukin, interleukin, interleukin, interleukin, interleukin, interleukin, interleukin, interleukin, interleukin,

A particularly preferred combination partner of the bispecific binding molecule of the invention is (Avastin ^®) VEGF antagonists, such as bevacizumab map, bar tapes (Vargatef) ^®, a seashell penip and sunitinib.

The efficacy of the bispecific binding molecules of the invention or polypeptides containing them, and compositions comprising them, can be determined using suitable in vitro assays, cell based assays, in vivo assays and / or known animal models or combinations thereof. Can be tested according to the specific disease or disorder of interest. Suitable assay and animal models are well known to those skilled in the art and include, for example, assays, such as the proliferation assays described herein and used in the following examples.

For example, the ELISA data of FIG. 10 showing that the affinity matured VHH completely blocks the hDLL4 / hNotch1-Fc interaction; IC ₅₀ (nM) value for affinity matured VHH in hDLL4 / hNotch1-Fc competition ELISA; And the affinity K _D (nM) of the purified affinity matured VHH for recombinant human DLL4 and mouse DLL4, the Dll4 binding components of the present invention are derived from the data obtained in the experiments of the present invention. It was confirmed that the characteristics superior to those of the molecule. This indicates that the Dll4 binding component of the present invention is a promising candidate with therapeutic efficacy in diseases and disorders associated with Dll4-mediated effects on angiogenesis such as cancer.

According to another embodiment of the present invention,

a) contacting the sample with the Dll4- and / or Ang2 binding component of the invention as defined above,

b) detecting the binding of the Dll4- and / or Ang2-binding component to the sample,

c) comparing the binding detected in step (b) with a standard and providing a method of diagnosing a disease wherein the difference in binding with respect to the sample is a diagnosis of a disease or disorder associated with a Dll4-mediated effect in angiogenesis.

In these and other uses, it may be useful to further denature the bispecific binding component of the invention, for example by inserting a functional group that is part of a specific binding pair, such as, for example, a biotin- (strep) avidin binding pair. have. Such functional groups can be used to link the bispecific binding molecules of the invention to other proteins, polypeptides or chemical compounds bound to the other half of a binding pair, ie by the formation of binding pairs. For example, the bispecific binding molecules of the present invention may be conjugated to biotin and linked to avidin or other proteins, polypeptides, compounds or carriers conjugated to streptavidin. For example, such conjugated bispecific binding molecules of the present invention can be used as reporters in diagnostic systems where the detectable signal generator is conjugated to avidin or streptavidin.

1: Amino acid sequence arrangement of human, bengal and cynomolgus monkey DLL4.
Figure 2: Human and mouse DLL4 deletion mutants (superscripts range in amino acid domain).
Figure 3: Purified VHH (ELISA) blocking hDLL4 / hNotch1-Fc interactions.
4: Purified VHH (AlphaScreen) blocking hDLL4 / hNotch1-Fc interaction.
Figure 5: Purified VHH (FMAT) blocking CHO-hDLL4 / hNotch1-Fc and CHO-mDLL4 / hNotch1-Fc interactions.
6: Purified VHH (reporter) blocking DLL4 mediated Notch1 digestion.
Figure 7: Binding of purified VHH with recombinant human and mouse DLL4 (ELISA).
Figure 8: Binding of purified VHH with recombinant human DLL1 and human Jagged-1 (ELISA).
Figure 9: Binding of purified VHH with human / mouse / cynomolgus monkey DLL4 (FACS).
10: Affinity mature VHH (ELISA) blocking hDLL4 / hNotch1-Fc interaction.
Figure 11: Purified affinity matured VHH (FMAT), blocking CHO-hDLL4 / hNotch1-Fc and CHO-mDLL4 / hNotch1-Fc interactions.
12: Binding of purified VHH with human / mouse DLL4 (ELISA).
13: Binding of purified human affinity VHH with recombinant human DLL1 and human Jagged-1 (ELISA).
14: Binding of purified VHH with human / mouse / cynomolgus monkey DLL4 (FACS).
15: Assessment of VHH effects on Dll4-mediated inhibition of HUVEC proliferation.
Figure 16: Description Cycle 1 DLL4xAng2 VHH
17: Purification cycle 1 DLL4xAng2 VHH (ELISA) blocking hDLL4-hNotch1 interaction
18: Purification cycle 1 DLL4xAng2 VHH (FMAT) blocking the CHO-hDLL4 / Notch1 (44-1) and CHO-mDLL4 / Notch1 (44-2) interactions
19: Purification cycle 1 DLL4xAng2 VHH (FACS) bound to human, mouse and cynomolgus monkey DLL4 overexpressing CHO cells
20: Purification cycle 1 DLL4xAng2 VHH (ELISA) bound to human, mouse and rat DLL4
21: Purification cycle 1 DLL4xAng2 VHH (ELISA) bound to human DLL1 and Jagged-1
22: Purification cycle 1 DLL4xAng2 VHH (ELISA) blocking hAng2-hTie2 (48-1), mAng2-mTie2 (48-2) and cAng2 / cTie2 (48-3) interactions
23: Description Cycle 2 DLL4xAng2 Bispecific VHHs
24: Purification cycle 2 DLL4xAng2 VHH (ELISA) blocking hDLL4-hNotch1 interaction
25: Purification cycle 2 DLL4xAng2 VHH (FMAT) blocking CHO-hDLL4 / Notch1 51-1 and CHO-mDLL4 / Notch1 51-2 interactions
26: Purification cycle 2 DLL4xAng2 VHH (reporter gene assay) blocking hDLL4-mediated Notch1 activation
27: Purification cycle 2 DLL4xAng2 VHH (FACS) bound to human, mouse and cynomolgus monkey DLL4 overexpressing CHO cells
28: Purification cycle 2 DLL4xAng2 VHH (ELISA) that binds to human, mouse and rat DLL4
29: Purification cycle 2 DLL4xAng2 VHH (ELISA) that binds to human DLL1 and Jagged-1
30: Purification cycle 2 DLL4xAng2 VHH (ELISA) blocking hAng2-hTie2 (56-1), mAng2-mTie2 (56-2) and cAng2 / cTie2 (56-3) interactions
31: Purification cycle 2 DLL4xAng2 VHH (ELISA) blocking hAng1-hTie2 interactions
32: Purification cycle 2 DLL4xAng2 VHH blocking hAng2-mediated HUVEC survival.

Materials and methods

a) Production of CHO and HEK293 cell lines overexpressing human, mouse and cynomolgus monkey Dll4

CDNAs encoding human (SEQ ID NO: 417; NM_019074.2) and mouse Dll4 (NM_019454.3) were obtained from the Human Adult Normal Tissue Heart cDNA library (BioChain, Hayward, CA, USA) and the Mouse Heart Tissue cDNA library (C57 / Bl6). Isolation from strains) was amplified from each using oligonucleotides designed within the 5 'and 3' UTRs of the corresponding sequences (see Table 1; SEQ ID NOs: 421-426). Amplicons were cloned into mammalian expression vector pCDNA3.1 (+)-neo (Invitrogen, Carlsbad, Calif., USA).

Cynomolgus monkey Dll4 cDNA from Cynomolgus Normal Tissue Heart cDNA library (BioChain, Hayward, Calif., USA), Dll4 coding sequence of closely related species Bengal monkey (Macaca mulatta Dll4, SEQ ID NO: 418; XM_001099250.1) (Table 1 Amplification using primers designed in 5 'and 3' UTRs. The final amplicon was cloned into the mammalian expression vector pCDNA3.1 (+)-neo (Invitrogen, Carlsbad, CA, USA). The amino acid sequence of the cynomolgus monkey Dll4 was found to be 100% identical to Bengal monkeys and 99% for humans (see FIG. 1: differences from human sequences are indicated by bold underlines).

Maternal CHO cells were constructed with pCDNA3.1 (+)-neo-hDll4, pcDNA3.1 (+) to construct Chinese Hamster Ovary (CHO) cells that overexpress human Dll4, mouse Dll4 or cynomolgus monkey Dll4. Electroporation with -neo-mDll4 or pcDNA3.1 (+)-neo-cDll4, respectively. Human embryonic kidney (HEK293) cells overexpressing human Dll4 and mouse Dll4 were generated by lipid mediated transfection in HEK293 parent cell lines with Fugene (Roche), respectively, of the pCDNA3.1 (+)-neo-hDll4 or mDll4 plasmids. Under all conditions, the transfectants were selected by addition of 1 mg / mL Geneticin (Invitrogen, Carlsbad, CA, USA).

b) Production of Monoclonal Anti-Dll4 IgG and Fab Fragments

US Patent 2008/0014196 (Genentech) describes a human / mouse cross-reactive Dll4 mAb used by Ridgway et al. (2006) to demonstrate the additional effects of VEGF mAb and Dll4 mAb on tumor growth in numerous xenograft models. It was. These anti-Dll4 mAbs and their corresponding Fabs were purified to characterize this antibody (fragment) in biochemical / cellular assays and xenograft models and in specific elution during phage selection. The published variable heavy and light chain sequences of Dll4 mAb were cloned into the hIgG2aκ framework and transiently expressed in HEK293 cells and purified from supernatant using Protein A chromatography. Purified Dll4 mAb was bound to human Dll4 and mouse Dll4 in ELISA and FACS (using CHO-mDll4 and CHO-hDll4 cells), sub-nanomol for both growth factor orthologue in Biacore nanomolar) affinity.

Corresponding Dll4 Fab fragments were prepared using Leto's Gene Optimization Software (www.entechelon.com) by gene assembly based on back-translation and codon optimization for expression in E. coli . Assembly PCR was performed by designing oligonucleotide primers for the assembly of variable light (V _L ), variable heavy (V _H ), constant light (C _L ) and normal domain 1 (C _H1 ) of heavy chains. The cDNA segment encoding V _L + C _L and V _H + C _H1 was added to the SfiI and AscI restriction sites in the pUC119 induction vector containing the LacZ promoter, kanamycin resistance gene, multiple cloning site and hybrid gIII-pelB leader sequence. It was cloned using KpnI and NotI restriction sites, respectively. In the frame with the Fab coding sequence, the expression vector encodes C-terminal HA and His6-tag. Fab fragments are expressed as His6-tagged proteins in E. coli and then purified by immobilized metal affinity chromatography (IMAC) and size exclusion chromatography (SEC) in culture medium. The relevant amino acid sequences of the variable heavy and variable light chains have been described (SEQ ID NOs: 1 and SEQ ID NO: 2, respectively, in US 2008/0014196); the amino acid sequences of intact heavy and light chains are shown in SEQ ID NOs: 419 and 420, respectively. It was.

c) production of Dll4 mutants for epitope mapping

Progressive deletion mutations in Dll4 ECD were generated to identify regions within the extracellular domain (ECD) of Dll4 that contain epitopes recognized by anti-Dll4 VHH. Mammalian expression vector pSecTag2 / Hygro (Invitrogen, Carlsbad, CA, USA) containing a CMV promoter top of a polynucleotide encoding a nested series of deletion fragments of Dll4 ECD fused to a polyHis-tag was subjected to standard recombinant DNA methods. (See FIG. 2: amino acid domain regions are indicated by superscript). Recombinant protein was expressed in transiently transfected HEK293 cells using the Freestyle 293 Expression System (Invitrogen, Carlsbad, Calif., USA), and the adjusted media were collected and purified by IMAC. Only Dll4 mutants without EGF2 like domains showed impaired binding to the humanized human / mouse cross-reactive anti-Dll4 mAb (immobilized by capturing anti-human IgG coated Biacore sensor chip). This IgG is known to have a specific binding epitope in the Dll4 domain (US Patent Publication No. 2008 / 0014196A1 by Genentech).

d) Production of Dll4 Reporter Assay Plasmids

The reporter assay is described basically based on the γ-secretase mediated degradation of Notch1 and nuclear translocation of Notch1's intracellular domain (NICD) upon stimulation with Dll4 (Struhl and Adachi, Cell. 1998 May 15; 93 (4): 649-60). Gal4 / VP16 coding sequence was introduced into NCID coding sequence. A powerful hybrid transcriptional activator GAL4-VP16 consisting of DNA binding fragments of yeast GAL4 fused to Herpes simple viral transcriptional activator domain VP16 was introduced at the carboxy terminal for the transmembrane region of Notch1. Degradation of this construct by γ-secretase releases the Gal4 / VP16 NICD fusion protein, which binds to and translocates to the nucleus where it binds and transactivates the cotransfected luciferase reporter plasmid, a potent GAL4-UAS promoter. Sequences (Struhl, G. and Adachi, A., Cell, vol. 93, 649-660, 1998). Human Notch1-Gal4 / VP16 expression cassettes were cloned into pcDNA3.1 (+)-neo (Invitrogen, Carlsbad, Calif., USA). A pGL4.31 [Luc2P / Gal4UAS / Hygro] vector (Promega, Madison, Wis., USA) was used as the luciferase reporter plasmid.

Example  One

In llama Humoral  Different species that elicit an immune response Dll4 Immunization

1.1 Immunization

After approval of the Ethical Committee of the faculty of Veterinary Medicine (University Ghent, Belgium), four llamas (designated 208, 209, 230, 231) were placed into six muscles of recombinant human Dll4 (R & D Systems, Minneapolis, MN, US). Immunization was done by intra injection (100 or 50 μg / dose weekly). Dll4 antigen was formulated in Stimune (Cedi Diagnostics BV, Lelystad, The Netherlands). Three different llamas (designated 127b, 260, 261) were immunized according to standard methods with four subcutaneous injections of CHO cells overexpressing denatured human Dll4 and mouse Dll4, constructed as described above. Cells were resuspended in D-PBS and ice-cold before injection. In addition, three other llamas (designated 282, 283, 284) were given four intramuscular injections of denatured recombinant human Dll4 and mouse Dll4 (R & D Systems, Minneapolis, MN, US) according to standard methods (100 every two weeks). Or 50 μg / dose). On day 0, the first injection of human Dll4 was formulated in Complete Freund's Adjuvant (Difco, Detroit, MI, USA) and subsequent injections into human and mouse Dll4 were formulated in Incomplete Freund's Adjuvant (Difco, Detroit, MI, USA).

1.2 Evaluation of Induced Immune Responses in Llama

To assess the induction of immune responses in animals against human Dll4 by ELISA, at llamas 208, 209, 230 and 231 on days 0 (preimmune), 21 and 43 (peripheral blood lymphocyte [PBL] collection time), Serum was collected at llamas 127b, 260 and 261 on days 0 and 51 and llamas 282, 283 and 284 on days 0, 28 and 50. In short, 2 μg / mL of recombinant human Dll4 or mouse Dll4 (R & D Systems, Minneapolis, MN, USA) were fixed in 96 well MaxiSorp plates (Nunc, Wiesbaden, Germany) overnight at 4 ° C. Wells were blocked with casein solution (1%). After addition of serum dilutions, the specifically bound immunoglobulin was conjugated with horseradish peroxidase (HRP) goat anti-lama immunoglobulin (Bethyl Laboratories Inc., Montgomery, TX, USA) and TMB substrate ( It was detected using subsequent enzymatic reactions in the presence of 3,3 ', 5,5'-tetramentylbenzidine) (Pierce, Rockford, IL, USA) and a significant antibody dependent immune response to Dll4 was induced. Antibody reactions are common antibodies and B-cell repertoires because specifically bound immunoglobulins can be detected with antibodies that specifically recognize either a common llama IgG1 antibody or a heavy chain-only llama IgG2 or IgG3 antibody (Table 2-A). Is initiated by an antibody of only the heavy chain that expresses. In all llamas injected with mouse Dll4, the antibody response is initiated by antibodies of only the heavy chain that express B-cells specifically for the general mouse Dll4. Serum titers of cell immunized animals are also confirmed by FACS analysis in HEK293 cells overexpressing human and mouse Dll4 (Table 2-B). The Dll4 serum titer for each llama is shown in Table 2.

Example  2

Heavy-chain  term- Dll4  Antibody fragment repertoire Cloning  And phage manufacturing

After the final immunization, the immunological tissue from which the B-cells producing heavy chain antibodies were harvested from the immunized llama. Typically, two 150 ml blood samples collected four and eight days after the last antigen injection, and one lymph node biopsy collected four days after the last antigen injection were collected in each animal. Peripheral blood mononuclear cells (PBMCs) in blood samples were prepared using Ficoll-Hypaque as directed by the manufacturer (Amersham Biosciences, Piscataway, NJ, USA). From PBMC and lymph node biopsies, total RNA was extracted and used as a starting material for RT-PCR to amplify the DNA segments encoding VHH as described in WO 05/044858. The total RNA isolated from all the immunized tissues of the animals collected for each immunized llama was collected to construct a library. In short, the PCR amplified VHH repertoire was cloned into a vector designed to facilitate phage display of the VHH library by specific restriction sites. This vector was derived from pUC119 and contains the LacZ promoter, M13 phage gIII protein coding sequence, resistance gene to ampicillin or carbenicillin, multiple cloning sites and hybrid gIII-pelB leader sequence (pAX050). In the frame with the VHH coding sequence, the vector codes for the C-terminal c-myc tag and the His6 tag. Phages were prepared according to standard methods and sterile filtered at 4 ° C for later use and stored.

Example  3

By phage display Dll4  Specific VHH Screening

VHH repertoire cloned as phage library, obtained in all llamas, was used for different selection strategies and various selection conditions were applied. The variables are: i) His-tagged recombinant express extracellular with the C-terminal of Dll4 protein format (human Dll4 (Met1-Pro524) and mouse Dll4 (Met1-Pro525) (R & D Systems, Minneapolis, MN, USA) Domain), or full-length human Dll4 and mouse Dll4, present in CHO or HEK293 cells overexpressing Dll4, ii) antigen presentation methods (plates coated directly with Dll4 or Neutravidin plates coated with Dll4 by biotin-tag; solution phase; Incubation in solution prior to capturing in Neutravidin coated plates, iii) antigen concentration, and iv) different elution methods (specific by non- or cognate receptor Notch1 / Fc chimera or anti-Dll4 IgG / Fab by trypsin). All selections were performed in Maxisorp 96 well plates (Nunc, Wiesbaden, Germany).

Selection was as follows: Dll4 antigen preparations for solid phase and solution phase selection formats were provided at various concentrations as described above. After 2 hours incubation with phage library and washing well, bound phage was eluted with trypsin (1 mg / mL) for 30 minutes. When trypsin was used for phage elution, protease activity was immediately neutralized using 0.8 mM protease inhibitor ABSF. For control, selective w / o antigens were performed simultaneously. E. coli was infected using phage results showing concentration against the default (non-antigen control). Infected E. coli cells were used to prepare phage in the next selection step (phage repair) or plated on agar plates (LB + amp + glucose ^2% ) for analysis of individual VHH clones. To screen the selection results for specific binders, single colonies were extracted from agar plates and incubated in 1 mL 96-deepwell plates. LacZ-regulated VHH expression was induced by addition of IPTG (final 0.1-1 mM) in the absence of glucose. Peripheral cytoplasmic extract (˜80 μL volume) was prepared according to standard methods.

Example  4

Dll4 - Notch1 AlphaScreen  And FMAT  compete In an assay  Screening of peripheral cytoplasmic extracts

Peripheral cytoplasmic extracts were screened in a human Dll4 / human Notch1 AlphaScreen assay to assess the blocking ability of expressed VHH. Biotinylation of Human Dll4 with Biotin (Sigma, St Louis, MO, USA) and Biotinamidohexanoic Acid 3-Sulfo-N-hydroxysuccinimide Ester Sodium Salt (Sigma, St Louis, MO, USA) It was. Notch1 / Fc chimeras (R & D Systems, Minneapolis, MN, USA) were captured using anti-Fc VHH bound to receptor beads according to manufacturer's instructions (Perkin Elmer, Waltham, Mass., US). Serial dilutions of periplasmic extracts were preincubated with biotinylated human Dll4 to assess the neutralization capacity of VHH. Receptor beads and streptavidin donor beads were added to this mixture and incubated for an additional hour at room temperature. Fluorescence was measured by reading the plates using an Envision Multilabel Plate Reader (Perkin Elmer, Waltham, Mass., USA) using an excitation wavelength of 680 nm and an emission wavelength of 520 nm. The decrease in fluorescence signal indicates that the binding of biotinylated human Dll4 to human Notch1 / Fc receptor was blocked by VHH expressed in the periplasmic extract.

Optionally, CHO-hDll4 and CHO-mDll4 cells were used in human Notch1 / Fc FMAT (Fluoro-metric Microvolume Assay Technology) competition assay. Recombinant human Notch1 / Fc chimeras (R & D Systems, Minneapolis, MN, USA) were randomly labeled with Alexa-647 (Invitrogen, Carlsbad, Calif., USA). In summary, 5 μL of periplasmic material was added to 7,500 CHO-hDll4 or CHO-mDll4 overexpressing cells and 100 pM or 175 pM of labeled human Notch1 / Fc, respectively, and read after incubation for 2 hours. To determine the noncompetitive baseline, inhibition rates were calculated from the baseline, including at least 30 replicates of cells with human Notch1 / Fc-Alexa647. All calculations were based on the FL1 total signal, including the mean of fluorescence per well time and the number of counts per well.

Inhibitory VHHs were selected and sequenced from this screening. Sequencing revealed 167 unique VHHs belonging to 40 different B-cell lineages. The total number of variants found in each B-cell lineage is listed in Table 3. A summary of the screening data of the periplasm is shown in Table 4. The amino acid sequences of all unique VHHs obtained are shown in Sequence Listing (SEQ ID NOs: 167-332 and 459) and Table 5 (CDR and framework region representations).

Example  5

The purified anti- Dll4 VHH Characterization

Inhibitory anti-Dll4 VHH selected in the screenings described in Example 4 was further purified and characterized. Selected VHH was expressed as c-myc, His6-tagged protein in E. coli TG1. 1 mM IPTG was added to induce expression and continued for 4 hours at 37 < 0 > C. After spinning the cell culture, the periplasmic extract was prepared by freezing the pellet. Using this extract as a starting material, VHH was purified by IMAC and size exclusion chromatography (SEC) to produce 95% SDS-PAGE purity.

5.1 Evaluation of VHH Blocking Dll4 in ELISA

The blocking ability of VHH was assessed by human Dll4-human Notch1 / Fc blocking ELISA. In summary, 1 μg / mL of human Notch1 / Fc chimera (R & D Systems, Minneapolis, MN, USA) was coated in 96-well MaxiSorp plates (Nunc, Wiesbaden, Germany). A fixed concentration of 15 nM biotinylated human Dll4 was preincubated with serial dilutions of VHH for 1 hour, then the mixture was incubated for an additional 1 hour in a coated Notch1 receptor. The remaining binding of biotinylated human Dll4 was detected using horseradish peroxidase (HRP) conjugated extravidin (Sigma, St. Louis, MO, USA) (FIG. 3). Human Dll4 was biotinylated as described above. IC ₅₀ values of VHH blocking the human Dll4-human Notch1 / Fc interactions are listed in Table 6.

5.2. Evaluation of Dll4 Blocking VHH in AlphaScreen

In summary, 1 nM biotinylated human Dll4 was captured in streptavidin coated donor beads (20 μg / mL) and 0.4 nM of receptor human Notch1 (Fc fusion protein) was anti-human Fc VHH coated receptor Captured in beads (20 μg / mL). Loaded both beads were incubated with dilution ranges of competing VHH (FIG. 4). The IC ₅₀ values of VHH blocking the human Dll4- human Notch1 / Fc interactions are listed in Table 7.

5.3 Inhibition of Human Notch1 / Fc Binding to Human or Mouse Dll4 Expressed on CHO Cells by Anti-Dll4 VHH

The blocking ability of VHH was assessed in human and mouse Dll4-human Notch1 / Fc competition FMAT assays as summarized in Example 4. (FIG. 5). The IC ₅₀ values of VHH blocking the interaction of human Notch1 / Fc with human or mouse Dll4 expressed in CHO cells are listed in Table 8.

5.4 Evaluation of Dll4 Blocking VHH in Reporter Assays

To assess the ability of selected VHHs, reporter assays based on Notch1's γ-secretase mediated degradation and secretion of Notch1's intracellular domain (NICD) upon stimulation with Dll4 were performed. Notch1-GAL4 / VP16 constructs were cotransfected with pGL4.31 [Luc2P / Gal4 UAS / Hygro] reporter plasmid in HEK cells to transiently express fusion proteins. Transiently transfected cells were stimulated by coculture with a stable HEK293-hDll4 cell line for 24 hours. Read 48 hours after transfection. VHH was preincubated with HEK293-hDll4 cells and included during coculture 1 hour prior to initiation of coculture (FIG. 6). Table 9 shows the IC ₅₀ values of VHH blocking Dll4-mediated degradation of Notch1 and subsequent translocation of its NICD to the receptor cell nucleus.

5.5 Epitope Binning

For example, when a benchmark antibody is bound, epitope binning experiments were performed to determine if VHH can bind to Dll4 simultaneously (using surface plasmon resonance (SPR) in the Biacore T100 instrument). Anti-Dll4 Fab fragments were irreversibly fixed to the active flow cells of the reference and CM5 sensor chips. For each sample (cycle) human Dll4 was injected into active and reference flow cells and reversibly captured with anti-Dll4 Fab. Further binding of VHH was assessed by injection on the fixed surface. All VHH and anti-Dll4 Fab were injected at 100 nM with a surface contact time of 120 seconds and a flow rate of 10 μL / min. The surface was regenerated using 10 mM glycine (pH 1.5). The progress curve was evaluated with Biacore T100 Evaluation software. Table 10-A shows the sequential injection / regeneration route of the analyzed VHH and control. VHH DLLBII56A09 (SEQ ID NO: 300), DLLBII96C03 (SEQ ID NO: 326), DLLBII101G08 (SEQ ID NO: 197) and DLLBII115A05 (SEQ ID NO: 224) did not appear to further bind to human Dll4 captured by Dll4 Fab. Injection of Dll4 Fab also failed to bind human Dll4 additionally, suggesting that all epitopes were saturated. Therefore, it can be concluded that this VHH recognizes an epitope that overlaps with the Dll4 Fab in binding human Dll4. Human-only VHH DLLBII6B11 (SEQ ID NO: 174) and DLLBII104G01 (SEQ ID NO: 215) show additional binding on Dll4 Fab capture human Dll4 such that VHH specific for human Dll4 recognizes an epitope different from human / mouse cross-reactive VHH Suggested.

5.6 Epitope Mapping Using Dll4 Deletion Mutants

The binding of VHH to Dll4 mutant was evaluated in Biacore. In summary, VHH DLLBII101G08 (SEQ ID NO: 197) and DLLBII115A5 (SEQ ID NO: 224) were coated onto a CM4 Sensorchip and 200 nM of each deletion mutant was injected through the chip. Binding was assessed qualitatively. The binding of DLLBII56A09 (SEQ ID NO: 300), DLLBII101G08 (SEQ ID NO: 197) and DLLBII115A05 (SEQ ID NO: 224) was not observed for human and mouse Dll4 mutants hDll4.1 and mDll4.8, respectively, and EGF- The pseudo 2 domain was deleted (Table 10-B). Indirect evidence using hDll4 / Dll4 IgG competition ELISA has already hit this observation. In summary, 1 μg / mL of Dll4 IgG was coated in 96 well MaxiSorp plates (Nunc, Wiesbaden, Germany). A fixed concentration of 6 nM biotinylated human Dll4 was preincubated with serial dilutions of VHH for 1 hour, then the mixture was incubated for an additional hour in coated IgG. The remaining binding of biotinylated human Dll4 was detected using horseradish peroxidase conjugated extravidin (Sigma, St. Louis, MO, USA) (data not shown). Human Dll4 was biotinylated as described above. It is known from the patent literature that the monoclonal anti-Dll4 IgG (Genentech, US Patent Publication 2008/00 14196A1) binds to epitopes in the EGF-like 2 domain of Dll4.

5.7 Affinity Measurement of the hDll4-VHH Interaction

Kinetic analysis to determine the affinity of the Dll4-VHH interaction was performed on the Biacore T100 instrument by surface plasmon resonance (SPR). Recombinant human Dll4 was immobilized by amine coupling (using EDC and NHS) on the CM5 chip or biotinylated human Dll4 was captured on the SA chip (streptavidin surface). Purified VHH or Fab fragments were injected at different concentrations (10-300 nM) for 2 minutes and dissociated at a flow rate of 45 μl / min for 20 minutes. Between sample injections, the surface was regenerated with 10 mM glycine pH 1.5 and 100 mM HCl. HBS-N (Hepes buffer pH 7.4) was used as running buffer. Where possible, data were evaluated by approximating a 1: 1 interaction model (Langmuir binding) to the binding curve. The affinity constant K _D was calculated from the resulting bond and dissociation rate constants (k _a ) and (k _d ). The affinity of anti-Dll4 VHH is listed in Table 11.

5.8 Binding to orthologues (mDll4, cDll4) and constituent members (hJagged-1, hDLL1)

Binding ELISA was performed to determine cross reactivity to mouse Dll4. In summary, recombinant mouse Dll4 (R & D Systems, Minneapolis, MS, USA) was coated in 96-well MaxiSorp plates (Nunc, Wiesbaden, Germany) at 1 μg / mL overnight at 4 ° C. Wells were blocked with casein solution (1% solution in PBS). VHH was applied as serial dilutions and binding was detected using mouse anti-myc (Roche) and anti-mouse-AP conjugates (Sigma, St Louis, MO, USA) (FIG. 7). As a reference, binding to human Dll4 was measured. Table 12 summarizes the EC ₅₀ values.

FACS binding experiments were performed to determine the cynomolgus monkey cross reactivity of VHH. HEK293 cells (transient or stable transfection) expressing cynomolgus monkey Dll4 were used for titration binding experiments of VHH. After incubation for 30 minutes under ice cooling, all samples were washed and detected by applying anti-c-myc ~ Alexa647 (Santa Cruz Biotechnology, Santa Cruz, CA, USA). HEK293 cells overexpressing human and mouse Dll4 were used as reference. Mean MCF values were measured in FACS arrays and used to calculate EC ₅₀ values (see FIG. 9).

The absence of binding to homologous ligands human DLL1 and human Jagged-1 was assessed by solid phase binding assay (ELISA). In summary, human DLL1 (Alexis, San Diego, CA, USA) and human Jagged-1 (Alexis, San Diego, CA, USA) were 96-well MaxiSorp plates (Nunc, Wiesbaden, Germany) at 1 μg / mL overnight at 4 ° C. )). Wells were blocked with casein solution (1% solution in PBS). VHH was applied as serial dilutions and binding was detected using mouse anti-myc (Roche) and anti-mouse-AP conjugates (Sigma, St Louis, MO, USA). All anti-Dll4 VHHs were considered nonreactive for this homologous ligand (FIG. 8).

5.9 Evaluation of VHH in Blocking of Dll4-mediated HUVEC Proliferation

The ability of selected VHHs is described by Ridgway et. al . , Nature. 2006 Dec 21; 444 (7122): 1083-7. In summary, 96 well tissue culture plates were prepared using purified Dll4-His (RnD Systems; C-terminal His-tagged human Dll4, amino acids 27-524, 0.75 ml / well, 10 ng in coated buffer (PBS, 0.1% BSA). / ml). Wells were washed with PBS and inoculated four times with 4000 HUVE cells / well. Cell proliferation was measured on day 4 by [ ³ H] -thymidine binding. The results shown in FIG. 15 demonstrate that DLL4 VHHs DLLBII101G08, DLLBII104G01, DLLBII115A05, DLLBII56A09 and DLL4 Fab inhibit the effect of DLL4 on HUVEC proliferation in a dose dependent manner. IC ₅₀ values are summarized in Table 13. The tested VHH completely inhibited the effect according to DLL4 at 10 μM.

Example  6

Selected Anti- Dll4 VHH Affinity mature

Two cycles of affinity maturation were performed for VHH DLLBII101G08 and DLLBII115A05.

In the first cycle, amino acid substitutions were randomly introduced into the framework (FW) and complementarity determining regions (CDR) using the error-prone PCR method. Mutations were performed using 1 ng of DLLBII101G08 or DLLBII115A05 cDNA template using a two round PCR based method (Genemorph II Random Mutagenesis kit, Stratagene, La Jolla, Calif., USA) and then using 0.1 ng of first round product A second error-prone PCR was performed. After the polish step, PCR products were introduced into vectors designed to facilitate phage display of the VHH library through intrinsic restriction sites. The next round of selection in solution was performed by reducing the concentrations of biotinylated recombinant human DLL4 (biot-rhDLL4) and trypsin eluate. A third round of affinity induced selection was also performed using cold rhDLL4 (at least 100 × excess than biot-rhDLL4). No screening for DLL4 in mice was included because cross-reactivity (preservation) was evaluated at the screening level. Each mutant was produced as a recombinant protein using an expression vector derived from pUC119 containing a LacZ promoter, a gene resistant to ampicillin, multiple cloning sites and an ompA leader sequence (pAX50). E. coli TG1 cells were transformed with an expression vector library and plated on agar plates (LB + Amp + 2% glucose). Single colonies were harvested from agar plates and incubated in 1 mL 96 deep well plates. IPTG (1 mM) was added to induce VHH expression. Peripheral cytoplasmic extract (volume of ˜80 uL) was prepared according to standard methods and screened for binding to recombinant human and mouse Dll4 in a ProteOn (BioRad, Hercules, CA, USA) off rate assay. In summary, the GLC ProteOn Sensor chip was coated with recombinant human Dll4 (with reference channels L1 / L3) on "ligand channels" L2 and L4, and the "ligand channels" L3 and L6 were coated with mouse Dll4. Peripheral cytoplasmic extracts of the affinity matured clones were diluted 1/10 and injected by “analyte channel” A1-A6. Average off rates were calculated for wild-type clones present in the plate and used as a reference to calculate off rate improvement.

In the second cycle, the combinatorial library was generated by simultaneously randomizing the possible locations identified in cycle 1. To this end, full-length DLLBII101G8 or DLLBII 115A05 cDNA was synthesized using oligonucleotides (NNS) degenerate at randomized positions by overlapping PCR and subjected to repair PCR. A list of primers used to generate combinatorial libraries can be found in Table 14 and SEQ ID NOs: 427-457. Randomized VHH genes were introduced into phage display vectors (pAX50) using specific restriction sites as described above (Example 2). Peripheral cytoplasmic extracts of each VHH clone were prepared as described above.

Binding screening with recombinant human Dll4 in the ProteOn off rate assay identified clones with up to 38-fold (DLLBII101G08) and 11-fold (DLLBII115A05) improved off rates (Table 15).

The top DLLBII101G08 variant and the DLLBII115A05 variant were cloned into the expression vector pAX100 in a frame with C-terminal c-myc tag and (His) 6 tag. The off rate for recombinant mouse Dll4 was also improved. VHH was produced as His6 tagged protein in E. coli and purified by IMAC and SEC. The sequences are shown in Table 16-A (DLLBII101G08) and 16-B (DLLBII11A05), respectively.

Example  7

Refined affinity matured anti- Dll4 VHH Characterization

The affinity matured variants of VHH DLLBII101G08 and DLLBII115A05 were expressed and purified as described above (Example 6). VHH was converted into rhDLL1 / rhJAG1 binding ELISA and hDll4 / mDll4 / cynoDll4 FACS (Example 5.8; Table 20; FIGS. 12 and 13), rhDll4-rhNotch1 competitive ELISA (Example 5.1; Table 17; FIG. 10), competitive rhNotch1-CHO- Characterized in hDll4 FMAT (Example 5.3; Table 18; FIG. 11).

Characterization data is summarized in Table 21. Overall, the affinity matured VHHs showed a clear improvement in affinity and potency, while their binding to mDll4 and cyno Dll4 was maintained and no binding to hDLL1 or hJAG1 was observed.

Example  8

Using anti-serum albumin binding as half-life extension DLL4  And Ang2 Targeting Double specificity VHH Composition, production and characterization

In the first cycle, anti-DLL4 VHH DLLBII00018 (US 2011/0172398 A1) and Cycle 1 sequence optimization anti-Ang2 VHH 00042 (SEQ ID NO: 482), 00045 (SEQ ID NO: 484) and 00050 (SEQ ID NO: 483) The bispecific VHH DLLANGBII00001-00016 was generated as a building block. Gene fusion to serum albumin binding VHH was used as a half-life extension method. Building blocks were connected by 9 Gly-Ser flexible linkers. VHH was prepared and purified as described in Example 5. An overview of the format and sequence of all bispecific VHHs is shown in FIG. 16 and Table 22-A (linker sequence underlined), SEQ ID NOs: 460-475. Expression concentrations are shown in Table 22-B.

In order to analyze anti-DLL4 blocking properties in comparison with monovalent buildingblock DLLBII00018, all purified bispecific VHHs were tested for hDLL4 / hNotch1 competition ELISA (see Example 5.1 described in US 2011/0172398 A1) (FIG. 17) and CHO-hDLL4 / CHO-mDLL4 competition FMAT (see Example 5.3 described in US 2011/0172398 A1) (FIG. 18). ELISA competition assays were performed here with a fixed concentration of 8 nM biotinylated hDLL4. Both ELISA and FMAT competition assays were performed after preincubation with VHH and 12.5 μM and 25 μM of human serum albumin, respectively. The IC ₅₀ values and percent inhibition are summarized in Table 23.

In addition, FACS binding experiments were performed to determine cross-reactivity of bispecific VHH against mouse and cynomolgus DLL4. In short, CHO cells overexpressing mouse and cynomolgus DLL4 were used for titration binding experiments of VHH. After incubation for 30 minutes under ice cooling, all samples were washed and two-step detection was performed using anti-c-myc followed by labeled goat-anti mouse IgG-PE. CHO cells overexpressing human DLL4 were used as a reference. Mean MCF values were measured with a FACS array and used to calculate EC ₅₀ values (Table 24: FIG. 19).

Binding ELISA was performed to determine cross reactivity for mouse DLL4 and rat DLL4. In sum, recombinant mouse DLL4 (R & D Systems, Minneapolis, MI, USA) and rat DLL4 were coated overnight in 4 ° C., 96-well MaxiSorp plates (Nunc, Wiesbaden, Germany). The wells were blocked with 1% casein solution. Biotinylated anti-VHH 1A4 binding followed by extravidin-HRP was detected by applying VHH in serial dilutions. 1A4 is anti-VHH VHH (manufactured in-house by Ablynx NV). Binding to human DLL4 was measured as a reference. EC ₅₀ values are summarized in Table 25 and FIG. 20.

The absence of binding to homologous human ligands DLL1 and Jagged-1 was assessed by solid phase binding assay (ELISA). In sum, 1 μg / mL of recombinant human DLL1 (Alexis, San Diego, CA, USA) or recombinant human Jagged-1 (Alexis, San Diego, CA, USA) was placed overnight at 4 ° C. in 96-well MaxiSorp plates (Nunc, Wiesbaden). , Germany). Wells were blocked with 1% casein solution. Biotinylated anti-VHH 1A4 binding followed by extravidin-HRP was detected by applying VHH in serial dilutions. Both bispecific VHHs were considered to have no cross-reactivity to these homologous ligands. The results are shown in FIG. 21.

In order to analyze anti-Ang2 blocking properties in comparison with monovalent anti-Ang2 building blocks 00042, 00045 and 00050, all purified bispecific VHHs were human Ang2 / hTie2-Fc (FIGS. 22A-22G), mouse Ang2 / mTie2 (FIGS. 22H-22K) and cyno Ang2 / cTie2 (FIGS. 22L-22O) competition ELISA. This assay was also performed after incubation with VHH and 0.5 μM human serum albumin. IC ₅₀ values and percent inhibition are summarized in Table 26.

The affinity of certain DLL4-Ang2 bispecific VHHs for human serum albumin was measured (see Example 5) and described in Table 27. The affinity constant K _D was calculated from the resulting binding and dissociation constants k _a and k _d .

In a second cycle, building the anti-DLL4 VHH DLLBII00018 (US 2011/0172398 A1) and the final sequence optimization anti-Ang2 VHH 00921 (SEQ ID NO: 485), 00938 (SEQ ID NO: 486) and 00956 (SEQ ID NO: 488) Used as a block to generate the bispecific VHH DLLANGBII00017-00019. Gene fusion to serum albumin binding VHH was used as a half-life extension method. Building blocks were connected by 9 Gly-Ser flexible linkers. An overview of the format and sequence of all bispecific VHHs is shown in Figure 23 and Table 28 (linker sequence underlined), SEQ ID NOs: 476-478.

In order to analyze anti-DLL4 blocking properties in comparison with monovalent buildingblock DLLBII00018, all purified bispecific VHHs were tested for hDLL4 / hNotch1 competition ELISA (Example 5.1 as described in US 2011 / 0172398A1) (FIG. 24), CHO-hDLL4 / CHO-mDLL4 competition FMAT (Example 5.3 as described in US 2011 / 0172398A1) (FIG. 25) and hDLL4-mediated Notchl activation (reporter gene) assay (US Patent No. Example 5.4) as described in 2011 / 0172398A1) (FIG. 26). ELISA competition assays were performed here with a fixed concentration of 8 nM biotinylated hDLL4. ELISA competition assays, FMAT competition assays and reporter gene assays were also performed after preincubation with VHH with human serum albumin of 12.5 μM, 25 μM and 162 μM, respectively. IC ₅₀ values and percent inhibition are summarized in Table 29.

Binding to human DLL4, mouse DLL4 and rat DLL4 was assessed with Biacore. In short, kinetic analysis of bispecific VHH was performed by SPR on a Biacore T100 device. Recombinant human DLL4 (R & D Systems, Minneapolis, MI, USA) and mouse DLL4 (R & D Systems, Minneapolis, MI, USA) were immobilized with amine coupling on the CM5 chip. VHH was injected at different concentrations of 2.5-1,800 nM on these surfaces. Samples were injected for 2 minutes and digested at a flow rate of 45 μl / min for 20 minutes. Between sample injections, the surface was regenerated with 100 mM pulses of 10 mM glycine pH 1.5. Binding / dissociation data were evaluated by adjusting the 1: 1 interaction model (Langmuir binding). The affinity constant K _D was calculated from the obtained bond and dissociation rate constants k _a and k _d (Table 30).

In addition, FACS binding experiments were performed to determine cross-reactivity of bispecific VHH against mouse and cynomolgus DLL4. In short, CHO cells overexpressing mouse and cynomolgus DLL4 were used for titration binding experiments of VHH. After incubation for 30 minutes under ice cooling, all samples were washed and two-step detection using biotinylated anti-VHH 1A4 followed by PE labeled streptavidin. CHO cells overexpressing human DLL4 were used as a reference. Mean MCF values were measured with a FACS array and used to calculate EC ₅₀ values (Table 31: FIG. 27).

To determine cross reactivity for mouse DLL4 and rat DLL4, binding ELISA was performed. In sum, recombinant mouse DLL4 (R & D Systems, Minneapolis, MI, USA) and rat DLL4 were coated overnight in 4 ° C., 96-well MaxiSorp plates (Nunc, Wiesbaden, Germany). The wells were blocked with 1% casein solution. Biotinylated anti-VHH 1A4 binding followed by extravidin-HRP was detected by applying VHH in serial dilutions. Binding to human DLL4 was measured as a reference. EC ₅₀ values are summarized in Table 32 and FIG. 28.

The absence of binding to homologous human ligands DLL1 and Jagged-1 was assessed by solid phase binding assay (ELISA). In sum, 1 μg / mL of recombinant human DLL1 (Alexis, San Diego, CA, USA) or recombinant human Jagged-1 (Alexis, San Diego, CA, USA) were placed overnight at 4 ° C. in 96-well MaxiSorp plates (Nunc, Wiesbaden). , Germany). Wells were blocked with 1% casein solution. Biotinylated anti-VHH 1A4 binding followed by extravidin-HRP was detected by applying VHH in serial dilutions. Both bispecific VHHs were considered to have no cross-reactivity to these homologous ligands. The results are shown in FIG.

All of the purified bispecific VHHs were analyzed in human Ang2 / hTie2 (FIGS. 30A-30C), mouse Ang2 / mTie2 (Anti-Ang2 blocking properties in comparison with final sequence optimization monovalent anti-Ang2 building blocks 00921, 00938 and 00956). 30D-30F), cyno Ang2 / cTie2 (FIGS. 30g-30i), hAng1 / hTie2 (FIG. 31) competition ELISA and hAng2-mediated HUVEC survival assays (FIG. 32). A summary of IC ₅₀ and% inhibition is shown in Table 33.

The affinity of DLLANGBII00017-18-19 for human, mouse, cynomolgus monkey and rat Ang2 (see Example 5) was measured and described in Table 34.

The affinities of DLLANGBII00017-18-19 to human, mouse and cynomolgus monkey serum albumin were measured (Example 5) and listed in Table 35. The affinity constant K _D was calculated from the obtained bond and dissociation rate constants k _a and k _d .

                         SEQUENCE LISTING <110> Boehringer Ingelheim International GmbH   <120> Bispecific binding molecules binding to Dll4 and Ang2 <130> 12-0331-pct <160> 540 <170> PatentIn version 3.3 <210> 1 <211> 16 <212> PRT <213> Homo sapiens <400> 1 Pro Phe Ala Tyr Tyr Ser Asp Leu Cys Gly Val Asn Gly Val Asp Tyr 1 5 10 15 <210> 2 <211> 16 <212> PRT <213> Lama Glama <400> 2 Pro Phe Ser Tyr Tyr Ser His Leu Cys Gly Val Asn Gly Tyr Asp Tyr 1 5 10 15 <210> 3 <211> 16 <212> PRT <213> Lama Glama <400> 3 Pro Phe Ser Tyr Tyr Ser Ser Leu Cys Gly Val Asn Glu Tyr Asp Tyr 1 5 10 15 <210> 4 <211> 15 <212> PRT <213> Lama Glama <400> 4 Pro Trp Asp Ser Trp Tyr Cys Gly Ile Gly Asn Asp Tyr Asp Tyr 1 5 10 15 <210> 5 <211> 16 <212> PRT <213> Lama Glama <400> 5 Pro Phe Ile His Tyr Ser Asp Leu Cys Gly Val Asn Gly Tyr Asp Tyr 1 5 10 15 <210> 6 <211> 22 <212> PRT <213> Lama Glama <400> 6 Asp Pro Ile His Asn Cys Tyr Ser Gly Ser Ser Tyr Tyr Tyr Ser Pro 1 5 10 15 Glu Ala Val Tyr Asp Tyr             20 <210> 7 <211> 16 <212> PRT <213> Lama Glama <400> 7 Pro Phe Ala His Tyr Ser Asp Leu Cys Gly Val Asn Gly Tyr Asp Tyr 1 5 10 15 <210> 8 <211> 15 <212> PRT <213> Lama Glama <400> 8 Ser Gly Ser Tyr Tyr Tyr Pro Thr Asp Val His Glu Tyr Asp Tyr 1 5 10 15 <210> 9 <211> 16 <212> PRT <213> Lama Glama <400> 9 Pro Phe Glu Tyr Tyr Ser Asp Leu Cys Gly Val Asn Gly Tyr Asp Tyr 1 5 10 15 <210> 10 <211> 21 <212> PRT <213> Lama Glama <400> 10 Asp Pro Ile His Asn Cys Tyr Ser Gly Arg Tyr Tyr Tyr Ser Pro Glu 1 5 10 15 Ala Val Tyr Glu Tyr             20 <210> 11 <211> 16 <212> PRT <213> Lama Glama <400> 11 Pro Phe Ser His Tyr Ser Asp Leu Cys Gly Val Asn Ala Ile Asp Tyr 1 5 10 15 <210> 12 <211> 16 <212> PRT <213> Lama Glama <400> 12 Pro Phe Glu Tyr Tyr Ser Asp Leu Cys Gly Val Asn Gly Tyr Asp Tyr 1 5 10 15 <210> 13 <211> 15 <212> PRT <213> Lama Glama <400> 13 Ser Gly Ser Tyr Tyr Tyr Pro Thr Asp Val Phe Glu Tyr Asp Tyr 1 5 10 15 <210> 14 <211> 21 <212> PRT <213> Lama Glama <400> 14 His Pro Leu Gln Asn Cys Cys Gly Gly Ser Ala Tyr Ala Ser Pro Glu 1 5 10 15 Ala Val Tyr Glu Tyr             20 <210> 15 <211> 16 <212> PRT <213> Lama Glama <400> 15 Pro Phe Ala Tyr Tyr Ser Asn Leu Cys Gly Val Asn Gly Tyr Asp Tyr 1 5 10 15 <210> 16 <211> 21 <212> PRT <213> Lama Glama <400> 16 Asp Pro Ile His Asn Cys Tyr Ser Gly Asn Tyr Tyr Ala Ser Pro Glu 1 5 10 15 Ala Val Tyr Asp Tyr             20 <210> 17 <211> 15 <212> PRT <213> Lama Glama <400> 17 Asp Pro Leu Val Cys Gly Tyr Asn Asp Pro Arg Leu Ala Asp Tyr 1 5 10 15 <210> 18 <211> 16 <212> PRT <213> Lama Glama <400> 18 Pro Phe Ala His Tyr Ser Asp Leu Cys Gly Val Asn Gly Tyr Asp Tyr 1 5 10 15 <210> 19 <211> 16 <212> PRT <213> Lama Glama <400> 19 Pro Phe Thr His Tyr Ser Asp Leu Cys Gly Val Asn Glu Tyr Asp Tyr 1 5 10 15 <210> 20 <211> 11 <212> PRT <213> Lama Glama <400> 20 Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr 1 5 10 <210> 21 <211> 11 <212> PRT <213> Lama Glama <400> 21 Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr 1 5 10 <210> 22 <211> 14 <212> PRT <213> Lama Glama <400> 22 Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Gly Tyr 1 5 10 <210> 23 <211> 15 <212> PRT <213> Lama Glama <400> 23 Ser Phe Gln Ser Gly Ala Ala Pro Gly Ala Asn Phe Tyr Asp Tyr 1 5 10 15 <210> 24 <211> 12 <212> PRT <213> Lama Glama <400> 24 Pro Ala Pro Gly Ser Ser Gly Tyr Glu Tyr Asp Tyr 1 5 10 <210> 25 <211> 12 <212> PRT <213> Lama Glama <400> 25 Pro Ser Pro Gly Ser Ser Gly Tyr Glu Tyr Asp Tyr 1 5 10 <210> 26 <211> 14 <212> PRT <213> Lama Glama <400> 26 Ser Leu Arg Gly Trp Asp Thr Thr Arg Ile Asp Tyr Glu Tyr 1 5 10 <210> 27 <211> 11 <212> PRT <213> Lama Glama <400> 27 Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr 1 5 10 <210> 28 <211> 14 <212> PRT <213> Lama Glama <400> 28 Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Gly Tyr 1 5 10 <210> 29 <211> 12 <212> PRT <213> Lama Glama <400> 29 Pro Ala Pro Gly Ser Ser Gly Tyr Glu Tyr Asp Tyr 1 5 10 <210> 30 <211> 12 <212> PRT <213> Lama Glama <400> 30 Pro Ser Pro Gly Ser Ser Gly Tyr Glu Tyr Asp Tyr 1 5 10 <210> 31 <211> 14 <212> PRT <213> Lama Glama <400> 31 Arg Ala Ala Asp Thr Arg Leu Gly Pro Tyr Glu Tyr Asp Tyr 1 5 10 <210> 32 <211> 14 <212> PRT <213> Lama Glama <400> 32 Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Gly Tyr 1 5 10 <210> 33 <211> 11 <212> PRT <213> Lama Glama <400> 33 Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr 1 5 10 <210> 34 <211> 13 <212> PRT <213> Lama Glama <400> 34 Gly Arg Gly Phe Tyr His Asp Tyr Ser Ser Tyr Glu Tyr 1 5 10 <210> 35 <211> 9 <212> PRT <213> Lama Glama <400> 35 Gly Pro Asp Cys Ser Ser Tyr Asp Tyr 1 5 <210> 36 <211> 14 <212> PRT <213> Lama Glama <400> 36 Ser Leu Arg Gly Trp Asp Thr Thr Arg Ile Asp Tyr Glu Tyr 1 5 10 <210> 37 <211> 13 <212> PRT <213> Lama Glama <400> 37 Ala Arg Gly Asp Ile Asp Val Tyr Thr Leu Ser Asp Ser 1 5 10 <210> 38 <211> 13 <212> PRT <213> Lama Glama <400> 38 Ala Arg Gly Asp Ile Asp Val Tyr Thr Leu Ser Asp Ser 1 5 10 <210> 39 <211> 14 <212> PRT <213> Lama Glama <400> 39 Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Gly Tyr 1 5 10 <210> 40 <211> 20 <212> PRT <213> Lama Glama <400> 40 Arg Leu Phe Ser Gly Gly Cys Ala Val Val Ala Gly Thr Ser Trp Ala 1 5 10 15 Asp Phe Gly Ser             20 <210> 41 <211> 20 <212> PRT <213> Lama Glama <400> 41 Arg Leu Phe Lys Gly Gly Cys Ala Val Val Ala Gly Thr Ser Trp Ala 1 5 10 15 Asp Phe Gly Ser             20 <210> 42 <211> 12 <212> PRT <213> Lama Glama <400> 42 Leu Ala Thr Thr Val Val Pro Ser Trp Val Asn Tyr 1 5 10 <210> 43 <211> 14 <212> PRT <213> Lama Glama <400> 43 Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Asp Tyr 1 5 10 <210> 44 <211> 14 <212> PRT <213> Lama Glama <400> 44 Ser Leu Arg Gly Trp Asp Thr Thr Trp Ile Asp Tyr Glu Tyr 1 5 10 <210> 45 <211> 13 <212> PRT <213> Lama Glama <400> 45 Asp Ser Arg Arg Gly Gly Val Gly Asn Phe Phe Arg Ser 1 5 10 <210> 46 <211> 14 <212> PRT <213> Lama Glama <400> 46 Pro Arg Gly Trp Gly Pro Thr Gly Pro Ile Glu Tyr Ala Tyr 1 5 10 <210> 47 <211> 8 <212> PRT <213> Lama Glama <400> 47 Arg Arg Asn Phe Leu Ser Asn Tyr 1 5 <210> 48 <211> 11 <212> PRT <213> Lama Glama <400> 48 Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr 1 5 10 <210> 49 <211> 14 <212> PRT <213> Lama Glama <400> 49 Ala Trp Cys Asp Ser Ser Trp Tyr Arg Ser Phe Val Gly Tyr 1 5 10 <210> 50 <211> 20 <212> PRT <213> Lama Glama <400> 50 Arg Leu Phe Ser Gly Gly Cys Ala Val Val Ala Arg Thr Ser Trp Ala 1 5 10 15 Asp Phe Gly Ser             20 <210> 51 <211> 11 <212> PRT <213> Lama Glama <400> 51 Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr 1 5 10 <210> 52 <211> 14 <212> PRT <213> Lama Glama <400> 52 Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Gly Tyr 1 5 10 <210> 53 <211> 11 <212> PRT <213> Lama Glama <400> 53 Pro Val Lys Val Ala Gly Leu Glu Tyr Ala Tyr 1 5 10 <210> 54 <211> 13 <212> PRT <213> Lama Glama <400> 54 Asp Val Gln His Ser Ala Trp Leu Lys Pro Leu Thr Tyr 1 5 10 <210> 55 <211> 3 <212> PRT <213> Lama Glama <400> 55 Asp Ile Tyr One <210> 56 <211> 15 <212> PRT <213> Lama Glama <400> 56 Pro Tyr Tyr Ser Asp Phe Glu Gly Thr Thr Thr Thr Glu Tyr Asp Tyr 1 5 10 15 <210> 57 <211> 16 <212> PRT <213> Lama Glama <400> 57 Thr Thr Arg Gly Arg Tyr Ser Ala Leu Ser Ala Ser Ala Tyr Asp Tyr 1 5 10 15 <210> 58 <211> 19 <212> PRT <213> Lama Glama <400> 58 Asp Arg Tyr Ile Arg Ala Arg Gln Gly Asp Tyr Trp Gly Ala Tyr Glu 1 5 10 15 Tyr Asp Tyr              <210> 59 <211> 21 <212> PRT <213> Lama Glama <400> 59 Asp Pro Ile His Asn Cys Tyr Ser Gly Arg Tyr Tyr Ala Ser Pro Asp 1 5 10 15 Ala Val Tyr Asp Tyr             20 <210> 60 <211> 15 <212> PRT <213> Lama Glama <400> 60 Asp Pro Leu Val Cys Gly Tyr Asn Asp Pro Arg Leu Ala Asp Tyr 1 5 10 15 <210> 61 <211> 16 <212> PRT <213> Lama Glama <400> 61 Pro Phe Asn His Tyr Ser Asp Leu Cys Gly Val Asn Ala Ile Asp Tyr 1 5 10 15 <210> 62 <211> 16 <212> PRT <213> Lama Glama <400> 62 Pro Phe Ser Tyr Tyr Ser Ser Leu Cys Gly Val Asn Glu Tyr Asp Tyr 1 5 10 15 <210> 63 <211> 16 <212> PRT <213> Lama Glama <400> 63 Pro Phe Ser Tyr Tyr Asn Asn Leu Cys Gly Val Asn Gly Val Asp Tyr 1 5 10 15 <210> 64 <211> 20 <212> PRT <213> Lama Glama <400> 64 Arg Leu Phe Ser Gly Gly Cys Ala Val Val Ala Gly Thr Ser Trp Ala 1 5 10 15 Asp Phe Gly Ser             20 <210> 65 <211> 16 <212> PRT <213> Lama Glama <400> 65 Pro Phe Ala His Tyr Ser Asp Leu Cys Gly Val Asn Gly Tyr Asp Tyr 1 5 10 15 <210> 66 <211> 16 <212> PRT <213> Lama Glama <400> 66 Pro Phe Ala Tyr Tyr Ser Asp Leu Cys Gly Val Asn Glu Tyr Asp Tyr 1 5 10 15 <210> 67 <211> 15 <212> PRT <213> Lama Glama <400> 67 Pro His Ser Asp Tyr Asp Glu Glu Ala Pro Ser Asp Phe Gly Ser 1 5 10 15 <210> 68 <211> 20 <212> PRT <213> Lama Glama <400> 68 Arg Leu Phe Ser Gly Gly Cys Ala Val Val Val Gly Thr Ser Trp Ala 1 5 10 15 Asp Phe Gly Ser             20 <210> 69 <211> 11 <212> PRT <213> Lama Glama <400> 69 Ser Leu Gly Ser Ser Trp Cys Ala Tyr Asp Tyr 1 5 10 <210> 70 <211> 15 <212> PRT <213> Lama Glama <400> 70 Asp Pro Leu Val Cys Gly Tyr Asn Asp Pro Arg Leu Ala Asp Tyr 1 5 10 15 <210> 71 <211> 20 <212> PRT <213> Lama Glama <400> 71 Arg Leu Phe Ser Gly Gly Cys Ala Val Val Ala Gly Thr Ser Trp Ala 1 5 10 15 Asp Phe Gly Ser             20 <210> 72 <211> 15 <212> PRT <213> Lama Glama <400> 72 Ser Gly Ser Tyr Tyr Tyr Pro Thr Asp Val His Glu Tyr Ala Tyr 1 5 10 15 <210> 73 <211> 16 <212> PRT <213> Lama Glama <400> 73 Pro Phe Glu Tyr Tyr Ser Ala Tyr Cys Gly Val Asn Arg Tyr Asp Tyr 1 5 10 15 <210> 74 <211> 18 <212> PRT <213> Lama Glama <400> 74 Ala His Asp Asn Tyr Trp Phe Thr Asp Asp Ser Leu Gly Arg Gly Leu 1 5 10 15 Lys Tyr          <210> 75 <211> 11 <212> PRT <213> Lama Glama <400> 75 Lys Thr Phe Gly Ser Asn Trp Tyr Asp Asp Tyr 1 5 10 <210> 76 <211> 21 <212> PRT <213> Lama Glama <400> 76 Asp Pro Ile His Asn Cys Tyr Ser Gly Arg Tyr Tyr Ala Ser Pro Glu 1 5 10 15 Ala Val Tyr Asp Tyr             20 <210> 77 <211> 21 <212> PRT <213> Lama Glama <400> 77 Asp Pro Phe His Asn Cys Tyr Ser Gly Ser His Tyr Ser Ser Pro Glu 1 5 10 15 Ala Val Tyr Glu Tyr             20 <210> 78 <211> 16 <212> PRT <213> Lama Glama <400> 78 Pro Phe Glu Tyr Tyr Ser Asp Leu Cys Gly Val Asn Gly Tyr Asp Tyr 1 5 10 15 <210> 79 <211> 16 <212> PRT <213> Lama Glama <400> 79 Pro Phe Asn Tyr Tyr Ser Asp Leu Cys Gly Val Asn Gly Val Asp Tyr 1 5 10 15 <210> 80 <211> 15 <212> PRT <213> Lama Glama <400> 80 Ser Gly Ser Tyr Tyr Tyr Pro Thr Asp Val His Glu Tyr Ala Tyr 1 5 10 15 <210> 81 <211> 16 <212> PRT <213> Lama Glama <400> 81 Pro Phe Ala His Tyr Ser Asp Leu Cys Gly Val Asn Gly Tyr Asp Tyr 1 5 10 15 <210> 82 <211> 8 <212> PRT <213> Lama Glama <400> 82 Glu Met Asp Gly Ser Arg Tyr Val 1 5 <210> 83 <211> 9 <212> PRT <213> Lama Glama <400> 83 Val His Pro Ser Thr Gly Phe Gly Ser 1 5 <210> 84 <211> 15 <212> PRT <213> Lama Glama <400> 84 Pro His Ser Asp Tyr Asp Glu Glu Ala Pro Ser Asp Phe Gly Ser 1 5 10 15 <210> 85 <211> 20 <212> PRT <213> Lama Glama <400> 85 Arg Leu Phe Ser Gly Gly Cys Ala Val Val Ala Ser Thr Ser Trp Ala 1 5 10 15 Asp Phe Gly Ser             20 <210> 86 <211> 20 <212> PRT <213> Lama Glama <400> 86 Arg Leu Phe Arg Gly Gly Cys Ala Val Val Ala Gly Thr Ser Trp Ala 1 5 10 15 Asp Phe Gly Ser             20 <210> 87 <211> 15 <212> PRT <213> Lama Glama <400> 87 Asp Pro Leu Val Cys Gly Tyr Asn Asp Pro Arg Leu Ala Asp Tyr 1 5 10 15 <210> 88 <211> 21 <212> PRT <213> Lama Glama <400> 88 Asp Pro Ile His Asn Cys Tyr Ser Gly Arg Tyr Tyr Ala Ser Pro Asp 1 5 10 15 Ala Val Tyr Glu Tyr             20 <210> 89 <211> 21 <212> PRT <213> Lama Glama <400> 89 Asp Pro Ile His Asn Cys Tyr Ser Gly Asn Gly Tyr Asp Ser Pro Glu 1 5 10 15 Ala Val Tyr Asp Tyr             20 <210> 90 <211> 21 <212> PRT <213> Lama Glama <400> 90 Asp Pro Phe His Asn Cys Tyr Ser Gly Ser Ala Tyr Ser Ser Pro Glu 1 5 10 15 Ala Val Tyr Glu Tyr             20 <210> 91 <211> 11 <212> PRT <213> Lama Glama <400> 91 Pro Val Lys Val Ala Gly Leu Glu Tyr Asp Tyr 1 5 10 <210> 92 <211> 11 <212> PRT <213> Lama Glama <400> 92 Ser Val Gly Ser Ser Trp Cys Ala Tyr Asp Tyr 1 5 10 <210> 93 <211> 11 <212> PRT <213> Lama Glama <400> 93 Ser Leu Gly Ser Ser Trp Cys Ala Tyr Asp Tyr 1 5 10 <210> 94 <211> 14 <212> PRT <213> Lama Glama <400> 94 Asp Ser Leu Pro Cys Tyr Tyr Asp Lys Met Val Tyr Asp Tyr 1 5 10 <210> 95 <211> 14 <212> PRT <213> Lama Glama <400> 95 Asp Ser Phe Ala Cys Asp Tyr Gly Lys Met Ile Tyr Asp Tyr 1 5 10 <210> 96 <211> 11 <212> PRT <213> Lama Glama <400> 96 Ser Leu Gly Ser Ser Trp Cys Ala Tyr Asp Tyr 1 5 10 <210> 97 <211> 15 <212> PRT <213> Lama Glama <400> 97 Asp Pro Leu Val Cys Gly Tyr Asn Asp Pro Arg Leu Ala Asp Tyr 1 5 10 15 <210> 98 <211> 15 <212> PRT <213> Lama Glama <400> 98 Ser Gly Ser Tyr Tyr Tyr Pro Thr Asp Val His Glu Tyr Asp Tyr 1 5 10 15 <210> 99 <211> 16 <212> PRT <213> Lama Glama <400> 99 Pro Phe Asn Tyr Tyr Ser Asn Leu Cys Gly Val Asn Gly Val Asp Tyr 1 5 10 15 <210> 100 <211> 21 <212> PRT <213> Lama Glama <400> 100 Asp Pro Ile His Asn Cys Tyr Ser Gly Ser His Tyr Tyr Ser Pro Glu 1 5 10 15 Ala Val Tyr Glu Tyr             20 <210> 101 <211> 21 <212> PRT <213> Lama Glama <400> 101 Asp Pro Ile His Asn Cys Tyr Ser Gly Ser Asp Tyr Ala Ser Pro Glu 1 5 10 15 Ala Val Tyr Glu Tyr             20 <210> 102 <211> 16 <212> PRT <213> Lama Glama <400> 102 Pro Phe Ile His Tyr Ser Asp Leu Cys Gly Val Asn Gly Asn Asp Tyr 1 5 10 15 <210> 103 <211> 15 <212> PRT <213> Lama Glama <400> 103 Ser Gly Ser Tyr Tyr Tyr Pro Thr Asp Val His Glu Tyr Asp Tyr 1 5 10 15 <210> 104 <211> 14 <212> PRT <213> Lama Glama <400> 104 Ala Pro Ile Phe Glu Cys Pro Ser Gly Glu Ile Tyr Asp Tyr 1 5 10 <210> 105 <211> 21 <212> PRT <213> Lama Glama <400> 105 Asp Pro Ile His Asn Cys Tyr Ser Gly Thr Tyr Tyr Ala Ser Pro Glu 1 5 10 15 Ala Val Tyr Glu Tyr             20 <210> 106 <211> 21 <212> PRT <213> Lama Glama <400> 106 Asp Pro Ile His Asn Cys Tyr Ser Gly Ser Tyr Tyr Ala Ser Pro Glu 1 5 10 15 Ala Val Tyr Asp Tyr             20 <210> 107 <211> 15 <212> PRT <213> Lama Glama <400> 107 Ser Gly Ser Tyr Tyr Tyr Pro Thr Asp Val His Glu Tyr Ala Tyr 1 5 10 15 <210> 108 <211> 15 <212> PRT <213> Lama Glama <400> 108 Ser Gly Ser Tyr Tyr Tyr Pro Thr Asp Val His Glu Tyr Ala Tyr 1 5 10 15 <210> 109 <211> 16 <212> PRT <213> Lama Glama <400> 109 Pro Phe Ala Tyr Tyr Ser Asp Leu Cys Gly Val Asn Glu Tyr Asp Tyr 1 5 10 15 <210> 110 <211> 16 <212> PRT <213> Lama Glama <400> 110 Pro Phe Asn His Tyr Ser Phe Leu Cys Gly Val Asn Glu Tyr Asp Tyr 1 5 10 15 <210> 111 <211> 15 <212> PRT <213> Lama Glama <400> 111 Ser Gly Ser Tyr Tyr Tyr Pro Thr Glu Val Tyr Glu Tyr Asp Tyr 1 5 10 15 <210> 112 <211> 15 <212> PRT <213> Lama Glama <400> 112 Ser Gly Ser Tyr Tyr Tyr Pro Thr Asp Val His Glu Tyr Asp Tyr 1 5 10 15 <210> 113 <211> 16 <212> PRT <213> Lama Glama <400> 113 Pro Phe Glu Tyr Tyr Ser Asp Leu Cys Gly Val Asn Gly Tyr Asp Tyr 1 5 10 15 <210> 114 <211> 21 <212> PRT <213> Lama Glama <400> 114 Asp Pro Ile His Asn Cys Tyr Gly Gly Ser Tyr Tyr Ala Ser Pro Glu 1 5 10 15 Ala Val Tyr Glu Tyr             20 <210> 115 <211> 12 <212> PRT <213> Lama Glama <400> 115 Ala Gly Ala Ser Ser Trp Cys Phe Pro Pro Gly Tyr 1 5 10 <210> 116 <211> 21 <212> PRT <213> Lama Glama <400> 116 Asp Pro Ile His Asn Cys Tyr Ser Gly Ile Tyr Tyr Ala Ser Pro Glu 1 5 10 15 Ala Val Tyr Asp Tyr             20 <210> 117 <211> 15 <212> PRT <213> Lama Glama <400> 117 Ser Gly Ser Tyr Tyr Tyr Pro Thr Asp Val His Glu Tyr Asp Tyr 1 5 10 15 <210> 118 <211> 21 <212> PRT <213> Lama Glama <400> 118 Asp Pro Ile His Asn Cys Tyr Ser Gly Arg Tyr Tyr Ala Ser Pro Asp 1 5 10 15 Ala Val Tyr Asp Tyr             20 <210> 119 <211> 16 <212> PRT <213> Lama Glama <400> 119 Pro Phe Ser Tyr Tyr Ser Asp Leu Cys Gly Val Asn Gly Tyr Asp Tyr 1 5 10 15 <210> 120 <211> 15 <212> PRT <213> Lama Glama <400> 120 Ser Gly Ser Tyr Tyr Tyr Pro Ser Asp Val His Glu Tyr Asp Tyr 1 5 10 15 <210> 121 <211> 16 <212> PRT <213> Lama Glama <400> 121 Pro Phe Ser Tyr Tyr Ser Gly Leu Cys Gly Val Asn Gly Val Asp Tyr 1 5 10 15 <210> 122 <211> 11 <212> PRT <213> Lama Glama <400> 122 Ser Leu Gly Ser Ser Trp Cys Ala Tyr Asp Tyr 1 5 10 <210> 123 <211> 21 <212> PRT <213> Lama Glama <400> 123 Asp Pro Val His Asn Cys Tyr Ser Gly Arg Tyr Tyr Ala Ser Pro Asp 1 5 10 15 Ala Val Tyr Glu Tyr             20 <210> 124 <211> 15 <212> PRT <213> Lama Glama <400> 124 Ser Gly Ser Tyr Tyr Tyr Pro Thr Asp Val His Glu Tyr Ala Tyr 1 5 10 15 <210> 125 <211> 16 <212> PRT <213> Lama Glama <400> 125 Pro Phe Ser His Tyr Asn Asp Leu Cys Gly Val Asn Ala Ile Asp Tyr 1 5 10 15 <210> 126 <211> 21 <212> PRT <213> Lama Glama <400> 126 Asp Pro Ile His Asn Cys Tyr Ser Gly Asn Gly Tyr Asp Ser Pro Glu 1 5 10 15 Ala Val Tyr Asp Tyr             20 <210> 127 <211> 16 <212> PRT <213> Lama Glama <400> 127 Pro Phe Glu Tyr Tyr Ser Asp Leu Cys Gly Val Asn Gly Tyr Asp Tyr 1 5 10 15 <210> 128 <211> 16 <212> PRT <213> Lama Glama <400> 128 Pro Phe Glu Tyr Tyr Ser Asn Leu Cys Gly Val Asn Gly Tyr Asp Tyr 1 5 10 15 <210> 129 <211> 21 <212> PRT <213> Lama Glama <400> 129 Asp Pro Leu His Asn Cys Tyr Ser Gly Arg Gly Tyr Tyr Ser Pro Glu 1 5 10 15 Ala Val Tyr Glu Tyr             20 <210> 130 <211> 21 <212> PRT <213> Lama Glama <400> 130 Asp Pro Ile His Asn Cys Tyr Ser Gly Ser Tyr Tyr Ala Ser Pro Glu 1 5 10 15 Ala Val Tyr Glu Tyr             20 <210> 131 <211> 16 <212> PRT <213> Lama Glama <400> 131 Pro Phe Glu Tyr Tyr Ser Asn Leu Cys Gly Val Asn Gly Tyr Asp Tyr 1 5 10 15 <210> 132 <211> 11 <212> PRT <213> Lama Glama <400> 132 Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr 1 5 10 <210> 133 <211> 11 <212> PRT <213> Lama Glama <400> 133 Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr 1 5 10 <210> 134 <211> 11 <212> PRT <213> Lama Glama <400> 134 Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr 1 5 10 <210> 135 <211> 11 <212> PRT <213> Lama Glama <400> 135 Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr 1 5 10 <210> 136 <211> 11 <212> PRT <213> Lama Glama <400> 136 Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr 1 5 10 <210> 137 <211> 17 <212> PRT <213> Lama Glama <400> 137 Lys Pro Asn Leu Lys Tyr Gly Ser Tyr Trp Pro Pro Arg Gly Tyr Asp 1 5 10 15 Tyr      <210> 138 <211> 17 <212> PRT <213> Lama Glama <400> 138 Lys Pro Asn Leu Lys Tyr Gly Ser Thr Trp Pro Pro Arg Gly Tyr Asp 1 5 10 15 Tyr      <210> 139 <211> 17 <212> PRT <213> Lama Glama <400> 139 Lys Pro Asn Leu Lys Tyr Gly Ser Tyr Trp Pro Pro Arg Gly Tyr Asp 1 5 10 15 Tyr      <210> 140 <211> 17 <212> PRT <213> Lama Glama <400> 140 Lys Pro Asn Leu Lys Tyr Gly Ser Asp Trp Pro Pro Arg Gly Tyr Asp 1 5 10 15 Tyr      <210> 141 <211> 8 <212> PRT <213> Lama Glama <400> 141 Arg Thr Ser Arg Ser Pro Arg Pro 1 5 <210> 142 <211> 15 <212> PRT <213> Lama Glama <400> 142 Ser Asn Tyr Tyr Ser Val Tyr Asp Asp Arg Pro Val Met Asp Tyr 1 5 10 15 <210> 143 <211> 7 <212> PRT <213> Lama Glama <400> 143 Gly Ser Gly Ser Trp Gly Val 1 5 <210> 144 <211> 19 <212> PRT <213> Lama Glama <400> 144 Asn Glu Gly Tyr Cys Ser Gly Tyr Gly Cys Tyr Glu Asp Ser Gly Gln 1 5 10 15 Tyr Asp Tyr              <210> 145 <211> 19 <212> PRT <213> Lama Glama <400> 145 Asn Glu Gly Tyr Cys Ser Gly Tyr Gly Cys Tyr Glu Asp Ser Gly Gln 1 5 10 15 Tyr Asp Tyr              <210> 146 <211> 12 <212> PRT <213> Lama Glama <400> 146 Gly Gly Arg Ser Phe Leu Pro Phe Val Pro Ala Tyr 1 5 10 <210> 147 <211> 19 <212> PRT <213> Lama Glama <400> 147 Asn Glu Gly Tyr Cys Ser Gly Tyr Gly Cys Tyr Glu Asp Ser Gly Gln 1 5 10 15 Tyr Asp Tyr              <210> 148 <211> 19 <212> PRT <213> Lama Glama <400> 148 Asn Gly Gly Tyr Cys Ser Gly Tyr Gly Cys Tyr Glu Asp Ser Gly Gln 1 5 10 15 Tyr Asp Tyr              <210> 149 <211> 11 <212> PRT <213> Lama Glama <400> 149 Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr 1 5 10 <210> 150 <211> 11 <212> PRT <213> Lama Glama <400> 150 Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr 1 5 10 <210> 151 <211> 11 <212> PRT <213> Lama Glama <400> 151 Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr 1 5 10 <210> 152 <211> 14 <212> PRT <213> Lama Glama <400> 152 Pro Arg Gly Trp Gly Pro Thr Gly Pro Ile Glu Tyr Ala Tyr 1 5 10 <210> 153 <211> 14 <212> PRT <213> Lama Glama <400> 153 Pro Arg Gly Trp Gly Pro Thr Gly Pro Ile Glu Tyr Gly Tyr 1 5 10 <210> 154 <211> 14 <212> PRT <213> Lama Glama <400> 154 Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Gly Tyr 1 5 10 <210> 155 <211> 14 <212> PRT <213> Lama Glama <400> 155 Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Ala Tyr 1 5 10 <210> 156 <211> 12 <212> PRT <213> Lama Glama <400> 156 Pro Ala Pro Gly Ser Ser Gly Tyr Glu Tyr Asp Tyr 1 5 10 <210> 157 <211> 11 <212> PRT <213> Lama Glama <400> 157 Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr 1 5 10 <210> 158 <211> 14 <212> PRT <213> Lama Glama <400> 158 Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Ala Tyr 1 5 10 <210> 159 <211> 14 <212> PRT <213> Lama Glama <400> 159 Pro Arg Gly Trp Gly Pro Thr Gly Pro Leu Glu Tyr Gly Tyr 1 5 10 <210> 160 <211> 14 <212> PRT <213> Lama Glama <400> 160 Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Gly Tyr 1 5 10 <210> 161 <211> 14 <212> PRT <213> Lama Glama <400> 161 Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Gly Tyr 1 5 10 <210> 162 <211> 14 <212> PRT <213> Lama Glama <400> 162 Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Gly Tyr 1 5 10 <210> 163 <211> 14 <212> PRT <213> Lama Glama <400> 163 Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Gly Tyr 1 5 10 <210> 164 <211> 14 <212> PRT <213> Lama Glama <400> 164 Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Ala Tyr 1 5 10 <210> 165 <211> 14 <212> PRT <213> Lama Glama <400> 165 Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Gly Tyr 1 5 10 <210> 166 <211> 14 <212> PRT <213> Lama Glama <400> 166 Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Ala Tyr 1 5 10 <210> 167 <211> 125 <212> PRT <213> Lama Glama <400> 167 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Thr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Gly Ser Thr Asn Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Ala Tyr Tyr Ser Asp Leu Cys Gly Val Asn Gly Val             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 168 <211> 125 <212> PRT <213> Lama Glama <400> 168 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Asn Ser Ser Asp Gly Ser Thr Tyr Tyr Thr Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Ile Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Ser Tyr Tyr Ser His Leu Cys Gly Val Asn Gly Tyr             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 169 <211> 125 <212> PRT <213> Lama Glama <400> 169 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Gly Ser Thr Ala Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Ser Tyr Tyr Ser Ser Leu Cys Gly Val Asn Glu Tyr             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 170 <211> 124 <212> PRT <213> Lama Glama <400> 170 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ile Ser Gly Phe Thr Leu Asp Leu His             20 25 30 Val Ile Gly Trp Leu Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Trp Asp Ser Trp Tyr Cys Gly Ile Gly Asn Asp Tyr Asp             100 105 110 Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 171 <211> 125 <212> PRT <213> Lama Glama <400> 171 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Arg Gly Ser Asn Gly Ser Thr Gly Tyr Thr Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Ile His Tyr Ser Asp Leu Cys Gly Val Asn Gly Tyr             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 172 <211> 131 <212> PRT <213> Lama Glama <400> 172 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Lys Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Arg Gly Gly Ser Thr Tyr Tyr Val Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Ile His Asn Cys Tyr Ser Gly Ser Ser Tyr Tyr Tyr             100 105 110 Ser Pro Glu Ala Val Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr         115 120 125 Val Ser Ser     130 <210> 173 <211> 125 <212> PRT <213> Lama Glama <400> 173 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Thr Ser Ser Asn Gly Ser Thr Tyr Tyr Thr Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Ala His Tyr Ser Asp Leu Cys Gly Val Asn Gly Tyr             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 174 <211> 123 <212> PRT <213> Lama Glama <400> 174 Glu Val Gln Leu Val Glu Ser Glu Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ser Tyr             20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val         35 40 45 Ala Val Ile Ser Asn Gly Gly Ile Thr Asn Tyr Pro Asn Ser Val Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Phe                 85 90 95 Tyr Ser Gly Ser Tyr Tyr Tyr Pro Thr Asp Val His Glu Tyr Asp Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 175 <211> 125 <212> PRT <213> Lama Glama <400> 175 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Asn Ser Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Glu Tyr Tyr Ser Asp Leu Cys Gly Val Asn Gly Tyr             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 176 <211> 130 <212> PRT <213> Lama Glama <400> 176 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Ile         35 40 45 Ser Cys Ile Ser Ser Arg Gly Gly Ser Thr Phe Tyr Val Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Ile His Asn Cys Tyr Ser Gly Arg Tyr Tyr Tyr Ser             100 105 110 Pro Glu Ala Val Tyr Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr Val         115 120 125 Ser Ser     130 <210> 177 <211> 125 <212> PRT <213> Lama Glama <400> 177 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr His             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Ser Ser Ser Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Ser His Tyr Ser Asp Leu Cys Gly Val Asn Ala Ile             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 178 <211> 125 <212> PRT <213> Lama Glama <400> 178 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Asn Ser Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Glu Tyr Tyr Ser Asp Leu Cys Gly Val Asn Gly Tyr             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 179 <211> 123 <212> PRT <213> Lama Glama <400> 179 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Asn Ser Tyr             20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val         35 40 45 Ala Ala Phe Ser Thr Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Phe                 85 90 95 Tyr Ser Gly Ser Tyr Tyr Tyr Pro Thr Asp Val Phe Glu Tyr Asp Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 180 <211> 130 <212> PRT <213> Lama Glama <400> 180 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Leu Asp Tyr Tyr             20 25 30 Ala Val Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Arg Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Thr Ser Arg Asn Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala His Pro Leu Gln Asn Cys Cys Gly Gly Ser Ala Tyr Ala Ser             100 105 110 Pro Glu Ala Val Tyr Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr Val         115 120 125 Ser Ser     130 <210> 181 <211> 125 <212> PRT <213> Lama Glama <400> 181 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Asn Ser Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Ala Tyr Tyr Ser Asn Leu Cys Gly Val Asn Gly Tyr             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 182 <211> 130 <212> PRT <213> Lama Glama <400> 182 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Leu Asp Tyr Tyr             20 25 30 Ala Val Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Arg Gly Gly Ser Thr Tyr Tyr Val Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Thr Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Ile His Asn Cys Tyr Ser Gly Asn Tyr Tyr Ala Ser             100 105 110 Pro Glu Ala Val Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val         115 120 125 Ser Ser     130 <210> 183 <211> 124 <212> PRT <213> Lama Glama <400> 183 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser His Asp Arg Thr Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Leu Val Cys Gly Tyr Asn Asp Pro Arg Leu Ala Asp             100 105 110 Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 184 <211> 125 <212> PRT <213> Lama Glama <400> 184 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Thr Ser Ser Tyr Gly Ser Thr Tyr Tyr Thr Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Ala His Tyr Ser Asp Leu Cys Gly Val Asn Gly Tyr             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 185 <211> 125 <212> PRT <213> Lama Glama <400> 185 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr His             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Gly Arg Thr Ala Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Thr His Tyr Ser Asp Leu Cys Gly Val Asn Glu Tyr             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 186 <211> 120 <212> PRT <213> Lama Glama <400> 186 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Pro Glu Gly Ile         35 40 45 Gly Cys Ile Ser Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr Trp Gly Gln             100 105 110 Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 187 <211> 120 <212> PRT <213> Lama Glama <400> 187 Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Pro Glu Gly Ile         35 40 45 Ser Cys Ile Ser Ser Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr Thr Gly Gln             100 105 110 Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 188 <211> 123 <212> PRT <213> Lama Glama <400> 188 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr             20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Thr Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Gly Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 189 <211> 124 <212> PRT <213> Lama Glama <400> 189 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asn Tyr             20 25 30 Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val         35 40 45 Ala Ala Ile Ser Trp Ser Gly Gly Asp Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Cys 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Ser Phe Gln Ser Gly Ala Ala Pro Gly Ala Asn Phe Tyr Asp             100 105 110 Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 190 <211> 121 <212> PRT <213> Lama Glama <400> 190 Glu Val Gln Leu Val Glu Ser Glu Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val         35 40 45 Ala Ala Ile Asn Trp Ser Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Ala Pro Gly Ser Ser Gly Tyr Glu Tyr Asp Tyr Trp Gly             100 105 110 Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 191 <211> 121 <212> PRT <213> Lama Glama <400> 191 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val         35 40 45 Ala Ala Ile Phe Trp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Ile Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Ser Pro Gly Ser Ser Gly Tyr Glu Tyr Asp Tyr Trp Gly             100 105 110 Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 192 <211> 123 <212> PRT <213> Lama Glama <400> 192 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Asp 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Asn Tyr             20 25 30 Arg Met Gly Trp Phe Arg Gln Gly Pro Gly Lys Glu Arg Glu Phe Val         35 40 45 Ala Ala Ile Gly Arg Asn Gly Gln Asn Thr Tyr Tyr Thr Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Val Thr Arg Asp Asn Ala Lys Asn Met Met Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Ser Ala Val Tyr Thr Cys                 85 90 95 Ala Ala Ser Leu Arg Gly Trp Asp Thr Thr Arg Ile Asp Tyr Glu Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 193 <211> 120 <212> PRT <213> Lama Glama <400> 193 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Asp Val Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Pro Glu Gly Ile         35 40 45 Ser Cys Ile Ser Ser Ser Gly Ser Ile Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Thr Ser Arg Asp Ser Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr Trp Gly Gln             100 105 110 Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 194 <211> 123 <212> PRT <213> Lama Glama <400> 194 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr             20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Asp Thr Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Gly Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 195 <211> 121 <212> PRT <213> Lama Glama <400> 195 Glu Val Gln Leu Val Glu Ser Arg Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Ser Tyr             20 25 30 Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val         35 40 45 Ala Thr Ile Asn Trp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Ala Pro Gly Ser Ser Gly Tyr Glu Tyr Asp Tyr Trp Gly             100 105 110 Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 196 <211> 121 <212> PRT <213> Lama Glama <400> 196 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val         35 40 45 Ala Ala Val Tyr Trp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Ser Pro Gly Ser Ser Gly Tyr Glu Tyr Asp Tyr Trp Gly             100 105 110 Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 197 <211> 123 <212> PRT <213> Lama Glama <400> 197 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Ala Asp Thr Arg Leu Gly Pro Tyr Glu Tyr Asp Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 198 <211> 123 <212> PRT <213> Lama Glama <400> 198 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr             20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ile Thr Tyr Tyr Ala Asp Phe Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Gly Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 199 <211> 120 <212> PRT <213> Lama Glama <400> 199 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Pro Glu Gly Ile         35 40 45 Ser Cys Ile Ser Ser Ser Gly Gly Ile Thr Tyr Tyr Thr Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr Thr Gly Gln             100 105 110 Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 200 <211> 122 <212> PRT <213> Lama Glama <400> 200 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Ala Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Ser Thr Tyr             20 25 30 Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu His Glu Phe Val         35 40 45 Ser Ala Ile Gly Arg Gly Thr Gly Ala Thr Ser Tyr Gly Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Gln Leu Glu Asp Thr Gly Asp Tyr Tyr Cys                 85 90 95 Val Ala Gly Arg Gly Phe Tyr His Asp Tyr Ser Ser Tyr Glu Tyr Arg             100 105 110 Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 201 <211> 118 <212> PRT <213> Lama Glama <400> 201 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Gly Tyr Tyr             20 25 30 Thr Ile Val Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Lys Gly Val         35 40 45 Ser Cys Ile Ser Ser Arg Asp Gly Ser Arg Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Arg Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Gly Pro Asp Cys Ser Ser Tyr Asp Tyr Trp Gly Gln Gly Thr             100 105 110 Gln Val Thr Val Ser Ser         115 <210> 202 <211> 123 <212> PRT <213> Lama Glama <400> 202 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Asp 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Asn Tyr             20 25 30 Arg Met Gly Trp Phe Arg Gln Gly Pro Gly Lys Glu Arg Glu Phe Val         35 40 45 Ala Ala Ile Gly Arg Asn Gly Gln Asn Thr Tyr Tyr Thr Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Val Thr Arg Asp Asn Ala Lys Asn Met Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Ser Ala Val Tyr Thr Cys                 85 90 95 Ala Ala Ser Leu Arg Gly Trp Asp Thr Thr Arg Ile Asp Tyr Glu Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 203 <211> 121 <212> PRT <213> Lama Glama <400> 203 Glu Val Gln Leu Met Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Ser Arg Ile Thr Ser Gly Gly Arg Thr Thr Tyr Arg Asp Ser Val Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala                 85 90 95 Lys Ala Arg Gly Asp Ile Asp Val Tyr Thr Leu Ser Asp Ser Arg Gly             100 105 110 Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 204 <211> 121 <212> PRT <213> Lama Glama <400> 204 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Ser Arg Ile Thr Ser Gly Gly Arg Ala Thr Tyr Arg Asp Ser Val Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala                 85 90 95 Lys Ala Arg Gly Asp Ile Asp Val Tyr Thr Leu Ser Asp Ser Arg Gly             100 105 110 Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 205 <211> 123 <212> PRT <213> Lama Glama <400> 205 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr             20 25 30 Asp Met Ser Trp Val Arg Arg Pro Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Gly Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 206 <211> 129 <212> PRT <213> Lama Glama <400> 206 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Val Ser Ser Asn Asn Ala Asp Asp Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Val Arg Leu Phe Ser Gly Gly Cys Ala Val Val Ala Gly Thr Ser             100 105 110 Trp Ala Asp Phe Gly Ser Ser Gly Gln Gly Thr Gln Val Thr Val Ser         115 120 125 Ser      <210> 207 <211> 129 <212> PRT <213> Lama Glama <400> 207 Ala Val Gln Leu Val Glu Ser Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Gly Ser Thr His Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asp Lys Val Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Val Arg Leu Phe Lys Gly Gly Cys Ala Val Val Ala Gly Thr Ser             100 105 110 Trp Ala Asp Phe Gly Ser Thr Gly Gln Gly Thr Gln Val Thr Val Ser         115 120 125 Ser      <210> 208 <211> 119 <212> PRT <213> Lama Glama <400> 208 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asp Ile Pro Arg Ile Ala             20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val         35 40 45 Ala Thr Val Ser Asn Ala Ala Thr Thr Arg Tyr Ala Asp Ser Ala Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Val Ser Leu Gln 65 70 75 80 Met Asp Asn Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys Tyr Ser                 85 90 95 Leu Ala Thr Thr Val Val Pro Ser Trp Val Asn Tyr Trp Gly Gln Gly             100 105 110 Thr Gln Val Thr Val Ser Ser         115 <210> 209 <211> 123 <212> PRT <213> Lama Glama <400> 209 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Gly Tyr Tyr             20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Met Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Asp Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 210 <211> 123 <212> PRT <213> Lama Glama <400> 210 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Asp Ala Ser Gly Arg Gly Phe Ser Tyr Tyr             20 25 30 Arg Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val         35 40 45 Ala Ala Ile Gly Lys Ser Gly Arg Asn Thr Tyr Tyr Gly Asp Tyr Val     50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Thr Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Thr Cys                 85 90 95 Ala Ala Ser Leu Arg Gly Trp Asp Thr Thr Trp Ile Asp Tyr Glu Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 211 <211> 121 <212> PRT <213> Lama Glama <400> 211 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Ser Arg Ile Asp             20 25 30 Val Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val         35 40 45 Ala Ser Ile Ser Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Glu Tyr Phe Lys Asn Met Met Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Phe Glu Asp Thr Ala Val Tyr Tyr Cys Asn                 85 90 95 Ala Asp Ser Arg Arg Gly Gly Val Gly Asn Phe Phe Arg Ser Trp Gly             100 105 110 Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 212 <211> 123 <212> PRT <213> Lama Glama <400> 212 Glu Val Gln Leu Val Glu Ser Arg Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Ser Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ile Pro Arg Gly Trp Gly Pro Thr Gly Pro Ile Glu Tyr Ala Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 213 <211> 116 <212> PRT <213> Lama Glama <400> 213 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ala Gly Ser Thr Phe Ser Ser Tyr             20 25 30 Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val         35 40 45 Ala His Ile Ser Thr Arg Gly Ile Thr Tyr Tyr Ala Asp Ser Val Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Met Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn                 85 90 95 Thr Arg Arg Asn Phe Leu Ser Asn Tyr Trp Gly Gln Gly Thr Gln Val             100 105 110 Thr Val Ser Ser         115 <210> 214 <211> 120 <212> PRT <213> Lama Glama <400> 214 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Pro Glu Gly Ile         35 40 45 Ser Cys Ile Ser Ser Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Ser Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr Thr Gly Gln             100 105 110 Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 215 <211> 123 <212> PRT <213> Lama Glama <400> 215 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Ala Trp Cys Asp Ser Ser Trp Tyr Arg Ser Phe Val Gly Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 216 <211> 129 <212> PRT <213> Lama Glama <400> 216 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Asp Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asn Asn Ala Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Val Arg Leu Phe Ser Gly Gly Cys Ala Val Val Ala Arg Thr Ser             100 105 110 Trp Ala Asp Phe Gly Ser Ser Gly Gln Gly Thr Gln Val Thr Val Ser         115 120 125 Ser      <210> 217 <211> 120 <212> PRT <213> Lama Glama <400> 217 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Phe Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Pro Glu Glu Ile         35 40 45 Ser Cys Ile Ser Ser Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr Trp Gly Gln             100 105 110 Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 218 <211> 123 <212> PRT <213> Lama Glama <400> 218 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ser Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Asn Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Gly Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 219 <211> 119 <212> PRT <213> Lama Glama <400> 219 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Asn Tyr             20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val         35 40 45 Val Gly Ile Ser Ser Asp Gly Ser Thr His Tyr Ala Asp Ser Ala Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Tyr                 85 90 95 Val Pro Val Lys Val Ala Gly Leu Glu Tyr Ala Tyr Trp Gly Gln Gly             100 105 110 Thr Gln Val Thr Val Ser Ser         115 <210> 220 <211> 121 <212> PRT <213> Lama Glama <400> 220 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Glu Val Ser Gly Ser Ile Gly Ser Val Ser             20 25 30 Asp Met Arg Trp Tyr Arg Gln Ala Pro Gly Leu Gln Tyr Glu Leu Val         35 40 45 Ala Arg Ile Thr Ser Gly Ser Ile Thr Asp Tyr Ser Asp Ser Val Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn                 85 90 95 Ala Asp Val Gln His Ser Ala Trp Leu Lys Pro Leu Thr Tyr Trp Gly             100 105 110 Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 221 <211> 111 <212> PRT <213> Lama Glama <400> 221 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Arg Phe Ser Ile Asn             20 25 30 Gly Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Ala Val         35 40 45 Ala Thr Ile Thr Arg Gly Gly Ile Arg Asp Tyr Thr Asp Ser Val Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Ile Ala Arg Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Asn Leu Lys Pro Glu Asp Ser Ala Val Tyr Tyr Cys Asn                 85 90 95 Ile Asp Ile Tyr Trp Gly Arg Gly Thr Gln Val Thr Val Ser Ser             100 105 110 <210> 222 <211> 121 <212> PRT <213> Lama Glama <400> 222 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Phe Gly Arg Thr Pro Tyr Gly Met             20 25 30 Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala         35 40 45 Ile Thr Ser Asp Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg     50 55 60 Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ala Val Ser Leu Gln Met 65 70 75 80 Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ala Pro                 85 90 95 Tyr Tyr Ser Asp Phe Glu Gly Thr Thr Thr Thr Glu Tyr Asp Tyr Trp Gly             100 105 110 Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 223 <211> 128 <212> PRT <213> Lama Glama <400> 223 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Val Arg Ser Tyr             20 25 30 Ala Thr Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val         35 40 45 Ala Ala Leu Arg Trp Ser Ile Gly Ser Ile Ala Ser Val Tyr Tyr Asp     50 55 60 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Gly Asp Asn Ala Glu Asn 65 70 75 80 Thr Val Tyr Leu Gln Met Asn Ala Leu Lys Pro Glu Asp Thr Ala Ile                 85 90 95 Tyr Tyr Cys Ala Ser Thr Thr Arg Gly Arg Tyr Ser Ala Leu Ser Ala             100 105 110 Ser Ala Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 224 <211> 128 <212> PRT <213> Lama Glama <400> 224 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Arg Ser Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ser Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Phe Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Arg Tyr Ile Arg Ala Arg Gln Gly Asp Tyr Trp Gly Ala             100 105 110 Tyr Glu Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 225 <211> 130 <212> PRT <213> Lama Glama <400> 225 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Arg Gly Gly Ser Thr Tyr Tyr Glu Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Ile His Asn Cys Tyr Ser Gly Arg Tyr Tyr Ala Ser             100 105 110 Pro Asp Ala Val Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val         115 120 125 Ser Ser     130 <210> 226 <211> 124 <212> PRT <213> Lama Glama <400> 226 Lys Val Gln Leu Val Glu Ser Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser His Asp Gly Thr Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Leu Val Cys Gly Tyr Asn Asp Pro Arg Leu Ala Asp             100 105 110 Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 227 <211> 125 <212> PRT <213> Lama Glama <400> 227 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr His             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Ser Ser Ser Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Asn His Tyr Ser Asp Leu Cys Gly Val Asn Ala Ile             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 228 <211> 125 <212> PRT <213> Lama Glama <400> 228 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Gly Ser Thr Ala Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Gly Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Ser Tyr Tyr Ser Ser Leu Cys Gly Val Asn Glu Tyr             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 229 <211> 125 <212> PRT <213> Lama Glama <400> 229 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Ser Ser Thr Asn Gly Asn Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Arg Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Ser Tyr Tyr Asn Asn Leu Cys Gly Val Asn Gly Val             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 230 <211> 129 <212> PRT <213> Lama Glama <400> 230 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Asp Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asn Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Val Arg Leu Phe Ser Gly Gly Cys Ala Val Val Ala Gly Thr Ser             100 105 110 Trp Ala Asp Phe Gly Ser Ser Gly Gln Gly Thr Gln Val Thr Val Ser         115 120 125 Ser      <210> 231 <211> 125 <212> PRT <213> Lama Glama <400> 231 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Thr Ser Ser Asn Gly Ser Thr Tyr Tyr Thr Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Ala His Tyr Ser Asp Leu Cys Gly Val Asn Gly Tyr             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 232 <211> 125 <212> PRT <213> Lama Glama <400> 232 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Leu Asp Tyr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Gly Ser Thr Gly Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Ala Tyr Tyr Ser Asp Leu Cys Gly Val Asn Glu Tyr             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 233 <211> 123 <212> PRT <213> Lama Glama <400> 233 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Thr Ser Tyr             20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val         35 40 45 Ala Ala Ile Ser Ser Asp Asp Ser Thr Tyr Tyr Ala Asp Cys Val Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Tyr Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn                 85 90 95 Ala Pro His Ser Asp Tyr Asp Glu Glu Ala Pro Ser Asp Phe Gly Ser             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 234 <211> 129 <212> PRT <213> Lama Glama <400> 234 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Asp Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Val Arg Leu Phe Ser Gly Gly Cys Ala Val Val Val Gly Thr Ser             100 105 110 Trp Ala Asp Phe Gly Ser Ser Gly Gln Gly Thr Gln Val Thr Val Ser         115 120 125 Ser      <210> 235 <211> 120 <212> PRT <213> Lama Glama <400> 235 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Asn Tyr             20 25 30 Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Gly Thr Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Arg Leu Lys Pro Glu Asp Thr Ala Ile Tyr Tyr Cys                 85 90 95 Ala Leu Ser Leu Gly Ser Ser Trp Cys Ala Tyr Asp Tyr Trp Gly Gln             100 105 110 Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 236 <211> 124 <212> PRT <213> Lama Glama <400> 236 Glu Val Gln Leu Met Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Tyr Asp Gly Thr Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Leu Val Cys Gly Tyr Asn Asp Pro Arg Leu Ala Asp             100 105 110 Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 237 <211> 129 <212> PRT <213> Lama Glama <400> 237 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Pro Ile Gly Trp Leu Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Asp Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asn Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Val Arg Leu Phe Ser Gly Gly Cys Ala Val Val Ala Gly Thr Ser             100 105 110 Trp Ala Asp Phe Gly Ser Ser Gly Gln Gly Thr Gln Val Thr Val Ser         115 120 125 Ser      <210> 238 <211> 123 <212> PRT <213> Lama Glama <400> 238 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ser Tyr             20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val         35 40 45 Ala Val Ile Ser Ser Gly Asp Arg Thr Asn Tyr Leu Asp Ser Val Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Phe                 85 90 95 Tyr Ser Gly Ser Tyr Tyr Tyr Pro Thr Asp Val His Glu Tyr Ala Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 239 <211> 125 <212> PRT <213> Lama Glama <400> 239 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Ser Ser Gly Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Glu Tyr Tyr Ser Ala Tyr Cys Gly Val Asn Arg Tyr             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 240 <211> 127 <212> PRT <213> Lama Glama <400> 240 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ser Ser Gly Arg Thr Leu Leu Asn Tyr             20 25 30 Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val         35 40 45 Ser Gly Ile Asn Trp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Thr Val Tyr 65 70 75 80 Leu His Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Ala His Asp Asn Tyr Trp Phe Thr Asp Asp Ser Leu Gly Arg             100 105 110 Gly Leu Lys Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 241 <211> 120 <212> PRT <213> Lama Glama <400> 241 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ser Tyr             20 25 30 Ala Met Gly Trp Tyr Arg His Gln Ala Pro Gly Lys Gln Arg Glu Leu         35 40 45 Val Ala Ala Ile Ser Ser Asp Gly Ser Thr His Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Met Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Asn Thr Lys Thr Phe Gly Ser Asn Trp Tyr Asp Asp Tyr Trp Gly Gln             100 105 110 Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 242 <211> 130 <212> PRT <213> Lama Glama <400> 242 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Arg Gly Gly Ser Thr Tyr Tyr Thr Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Ile His Asn Cys Tyr Ser Gly Arg Tyr Tyr Ala Ser             100 105 110 Pro Glu Ala Val Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val         115 120 125 Ser Ser     130 <210> 243 <211> 130 <212> PRT <213> Lama Glama <400> 243 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Ala Phe Thr Leu Asp Tyr Tyr             20 25 30 Ala Val Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Ser Gly Gly Ser Thr Tyr Tyr Glu Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Phe His Asn Cys Tyr Ser Gly Ser His Tyr Ser Ser             100 105 110 Pro Glu Ala Val Tyr Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr Val         115 120 125 Ser Ser     130 <210> 244 <211> 125 <212> PRT <213> Lama Glama <400> 244 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Trp Val         35 40 45 Ser Cys Ile Asn Ser Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Glu Tyr Tyr Ser Asp Leu Cys Gly Val Asn Gly Tyr             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 245 <211> 125 <212> PRT <213> Lama Glama <400> 245 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Gly Arg Thr Asn Tyr Val Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Met Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Asn Tyr Tyr Ser Asp Leu Cys Gly Val Asn Gly Val             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 246 <211> 123 <212> PRT <213> Lama Glama <400> 246 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ser Tyr             20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Asn Gln Arg Glu Leu Val         35 40 45 Ala Val Ile Ser Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Cys Cys Phe                 85 90 95 Tyr Ser Gly Ser Tyr Tyr Tyr Pro Thr Asp Val His Glu Tyr Ala Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 247 <211> 125 <212> PRT <213> Lama Glama <400> 247 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Asn Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Thr Ser Ser Asn Gly Ser Thr Tyr Tyr Thr Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Ala His Tyr Ser Asp Leu Cys Gly Val Asn Gly Tyr             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 248 <211> 117 <212> PRT <213> Lama Glama <400> 248 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Asp 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Val Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Gln Gly Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Ser Ile Asn Ser Gly Val Gly Lys Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Phe Arg Asp Asn Ala Lys Asn Met Val Tyr 65 70 75 80 Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Glu Met Asp Gly Ser Arg Tyr Val Glu Gly Gln Gly Thr Gln             100 105 110 Val Thr Val Ser Ser         115 <210> 249 <211> 117 <212> PRT <213> Lama Glama <400> 249 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Glu Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Thr Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val         35 40 45 Ala Gly Ile Ser Phe Asp Gly Ser Thr His Tyr Ala Glu Ser Val Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Val Ser Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Ala Ala Val Tyr Tyr Cys Tyr                 85 90 95 Ser Val His Pro Ser Thr Gly Phe Gly Ser Trp Gly Gln Gly Thr Gln             100 105 110 Val Thr Val Ser Ser         115 <210> 250 <211> 123 <212> PRT <213> Lama Glama <400> 250 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Ser Thr Phe Thr Ser Tyr             20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val         35 40 45 Ala Ala Ile Ser Ser Asp Asp Ser Thr Tyr Tyr Ala Asp Cys Val Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn                 85 90 95 Ala Pro His Ser Asp Tyr Asp Glu Glu Ala Pro Ser Asp Phe Gly Ser             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 251 <211> 129 <212> PRT <213> Lama Glama <400> 251 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Asp Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asn Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Thr Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Val Arg Leu Phe Ser Gly Gly Cys Ala Val Val Ala Ser Thr Ser             100 105 110 Trp Ala Asp Phe Gly Ser Ser Gly Gln Gly Thr Gln Val Thr Val Ser         115 120 125 Ser      <210> 252 <211> 129 <212> PRT <213> Lama Glama <400> 252 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asn Asn Ala Lys Asn Arg Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Val Arg Leu Phe Arg Gly Gly Cys Ala Val Val Ala Gly Thr Ser             100 105 110 Trp Ala Asp Phe Gly Ser Ser Gly Gln Gly Thr Gln Val Thr Val Ser         115 120 125 Ser      <210> 253 <211> 124 <212> PRT <213> Lama Glama <400> 253 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Tyr Asp Gly Thr Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Leu Val Cys Gly Tyr Asn Asp Pro Arg Leu Ala Asp             100 105 110 Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 254 <211> 130 <212> PRT <213> Lama Glama <400> 254 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Arg Gly Gly Ser Thr Tyr Tyr Glu Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Ile His Asn Cys Tyr Ser Gly Arg Tyr Tyr Ala Ser             100 105 110 Pro Asp Ala Val Tyr Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr Val         115 120 125 Ser Ser     130 <210> 255 <211> 130 <212> PRT <213> Lama Glama <400> 255 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Arg Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Ile His Asn Cys Tyr Ser Gly Asn Gly Tyr Asp Ser             100 105 110 Pro Glu Ala Val Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val         115 120 125 Ser Ser     130 <210> 256 <211> 130 <212> PRT <213> Lama Glama <400> 256 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Phe His Asn Cys Tyr Ser Gly Ser Ala Tyr Ser Ser             100 105 110 Pro Glu Ala Val Tyr Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr Val         115 120 125 Ser Ser     130 <210> 257 <211> 119 <212> PRT <213> Lama Glama <400> 257 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Thr Tyr             20 25 30 Ala Met Gly Trp Tyr Arg Gln Asp Pro Gly Asn Gln Arg Glu Leu Val         35 40 45 Ala Ala Ile Ser Ser Asp Gly Ser Thr His Tyr Ala Asp Ser Val Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Tyr                 85 90 95 Ala Pro Val Lys Val Ala Gly Leu Glu Tyr Asp Tyr Trp Gly Gln Gly             100 105 110 Thr Gln Val Thr Val Ser Ser         115 <210> 258 <211> 120 <212> PRT <213> Lama Glama <400> 258 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Asn Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Ser Gly Phe Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Ser Val Gly Ser Ser Trp Cys Ala Tyr Asp Tyr Trp Gly Gln             100 105 110 Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 259 <211> 120 <212> PRT <213> Lama Glama <400> 259 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Glu Asn Tyr             20 25 30 Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Gly Thr Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Arg Leu Lys Pro Glu Asp Thr Ala Ile Tyr Tyr Cys                 85 90 95 Ala Leu Ser Leu Gly Ser Ser Trp Cys Ala Tyr Asp Tyr Trp Gly Gln             100 105 110 Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 260 <211> 123 <212> PRT <213> Lama Glama <400> 260 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Asn Tyr             20 25 30 Val Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Glu Val         35 40 45 Ser Cys Ile Ser Ser Ser Gly Gly Ser Thr Asp Tyr Leu Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Ser Leu Pro Cys Tyr Tyr Asp Lys Met Val Tyr Asp Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 261 <211> 123 <212> PRT <213> Lama Glama <400> 261 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Lys Leu Asp Tyr Tyr             20 25 30 Val Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Thr Ser Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met His Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Ser Phe Ala Cys Asp Tyr Gly Lys Met Ile Tyr Asp Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 262 <211> 120 <212> PRT <213> Lama Glama <400> 262 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Gly Phe Asp Asn Tyr             20 25 30 Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Ser Gly Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met His Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Ser Leu Gly Ser Ser Trp Cys Ala Tyr Asp Tyr Trp Gly Gln             100 105 110 Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 263 <211> 124 <212> PRT <213> Lama Glama <400> 263 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser His Asp Gly Thr Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Leu Val Cys Gly Tyr Asn Asp Pro Arg Leu Ala Asp             100 105 110 Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 264 <211> 123 <212> PRT <213> Lama Glama <400> 264 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ser Tyr             20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val         35 40 45 Ala Ala Ile Ser Asn Gly Gly Ser Thr Asn Tyr Val Asp Ser Val Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Phe                 85 90 95 Tyr Ser Gly Ser Tyr Tyr Tyr Pro Thr Asp Val His Glu Tyr Asp Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 265 <211> 125 <212> PRT <213> Lama Glama <400> 265 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Gly Arg Thr Asn Tyr Val Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Met Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Asn Tyr Tyr Ser Asn Leu Cys Gly Val Asn Gly Val             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 266 <211> 130 <212> PRT <213> Lama Glama <400> 266 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Asp Tyr Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Ile         35 40 45 Ser Cys Ile Ser Gly Arg Gly Gly Ser Thr Tyr Tyr Ile Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Ile His Asn Cys Tyr Ser Gly Ser His Tyr Tyr Ser             100 105 110 Pro Glu Ala Val Tyr Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr Val         115 120 125 Ser Ser     130 <210> 267 <211> 130 <212> PRT <213> Lama Glama <400> 267 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Asp 1 5 10 15 Ser Leu Arg Leu Ala Cys Ala Ala Ser Gly Phe Ala Leu Asp Tyr Tyr             20 25 30 Ala Val Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Arg Gly Gly Ser Thr Phe Tyr Ala Asp Ser Leu     50 55 60 Lys Gly Arg Phe Thr Thr Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Ile His Asn Cys Tyr Ser Gly Ser Asp Tyr Ala Ser             100 105 110 Pro Glu Ala Val Tyr Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr Val         115 120 125 Ser Ser     130 <210> 268 <211> 125 <212> PRT <213> Lama Glama <400> 268 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asp 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ala Cys Ile Arg Ser Ser Asp Gly Ser Thr Tyr Tyr Thr Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Ile His Tyr Ser Asp Leu Cys Gly Val Asn Gly Asn             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 269 <211> 123 <212> PRT <213> Lama Glama <400> 269 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Asn Ser Tyr             20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val         35 40 45 Ala Val Ile Ser Ser Gly Ser Val Thr Asn Tyr Ala Asp Ser Val Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Ser Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Phe                 85 90 95 Tyr Ser Gly Ser Tyr Tyr Tyr Pro Thr Asp Val His Glu Tyr Asp Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 270 <211> 123 <212> PRT <213> Lama Glama <400> 270 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Arg Leu Asp Tyr Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Met Gly Ser Ser Val Arg Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Ala Pro Ile Phe Glu Cys Pro Ser Gly Glu Ile Tyr Asp Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 271 <211> 130 <212> PRT <213> Lama Glama <400> 271 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Arg Gly Gly Ser Thr Tyr Tyr Thr Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Ile His Asn Cys Tyr Ser Gly Thr Tyr Tyr Ala Ser             100 105 110 Pro Glu Ala Val Tyr Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr Val         115 120 125 Ser Ser     130 <210> 272 <211> 130 <212> PRT <213> Lama Glama <400> 272 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Leu Asp Tyr Tyr             20 25 30 Ala Val Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Arg Gly Gly Ser Thr Tyr Tyr Val Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Thr Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Glu Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Ile His Asn Cys Tyr Ser Gly Ser Tyr Tyr Ala Ser             100 105 110 Pro Glu Ala Val Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val         115 120 125 Ser Ser     130 <210> 273 <211> 123 <212> PRT <213> Lama Glama <400> 273 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ser Tyr             20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val         35 40 45 Ala Val Ile Ser Ser Gly Asp Ser Thr Asn Tyr Ser Asp Ser Val Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Phe                 85 90 95 Tyr Ser Gly Ser Tyr Tyr Tyr Pro Thr Asp Val His Glu Tyr Ala Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 274 <211> 123 <212> PRT <213> Lama Glama <400> 274 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ser Phe Ser Ser Tyr             20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val         35 40 45 Ala Val Ile Ser Ser Gly Asp Arg Thr Asn Tyr Leu Asp Ser Val Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Phe                 85 90 95 Tyr Ser Gly Ser Tyr Tyr Tyr Pro Thr Asp Val His Glu Tyr Ala Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 275 <211> 125 <212> PRT <213> Lama Glama <400> 275 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Leu Asp Tyr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Ser Gly Ser Asp Gly Ser Thr Gly Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Ala Tyr Tyr Ser Asp Leu Cys Gly Val Asn Glu Tyr             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 276 <211> 125 <212> PRT <213> Lama Glama <400> 276 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Leu Asp Gly His             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Asn Ser Gly Asp Gly Ser Thr Gly Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Arg Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Asn His Tyr Ser Phe Leu Cys Gly Val Asn Glu Tyr             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 277 <211> 123 <212> PRT <213> Lama Glama <400> 277 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ser Tyr             20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Ala         35 40 45 Ala Val Ile Ser Thr Gly Asp Asn Thr Asn Tyr Ala Asp Ser Val Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr His Cys Phe                 85 90 95 Tyr Ser Gly Ser Tyr Tyr Tyr Pro Thr Glu Val Tyr Glu Tyr Asp Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 278 <211> 123 <212> PRT <213> Lama Glama <400> 278 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Arg Ser Tyr             20 25 30 Ala Met Gly Trp Tyr Arg Gln Val Pro Gly Asn Gln Arg Glu Leu Val         35 40 45 Ala Val Ile Ser Ser Gly Asp Ser Ala Asn Tyr Ala Asp Ser Val Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Phe                 85 90 95 Tyr Ser Gly Ser Tyr Tyr Tyr Pro Thr Asp Val His Glu Tyr Asp Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 279 <211> 125 <212> PRT <213> Lama Glama <400> 279 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Asn Ser Ser Asp Gly Thr Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Glu Tyr Tyr Ser Asp Leu Cys Gly Val Asn Gly Tyr             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 280 <211> 130 <212> PRT <213> Lama Glama <400> 280 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Gly Ala Ser Gly Phe Ser Leu Asp Tyr Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Gly Arg Gly Ser Asn Thr Tyr Tyr Leu Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Ile His Asn Cys Tyr Gly Gly Ser Tyr Tyr Ala Ser             100 105 110 Pro Glu Ala Val Tyr Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr Val         115 120 125 Ser Ser     130 <210> 281 <211> 120 <212> PRT <213> Lama Glama <400> 281 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala                 85 90 95 Ile Ala Gly Ala Ser Ser Trp Cys Phe Pro Pro Gly Tyr Trp Gly Gln             100 105 110 Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 282 <211> 130 <212> PRT <213> Lama Glama <400> 282 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Leu Asp Tyr Tyr             20 25 30 Ala Val Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Arg Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Thr Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Ile His Asn Cys Tyr Ser Gly Ile Tyr Tyr Ala Ser             100 105 110 Pro Glu Ala Val Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val         115 120 125 Ser Ser     130 <210> 283 <211> 123 <212> PRT <213> Lama Glama <400> 283 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ser Tyr             20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Val Lys Gln Arg Glu Leu Val         35 40 45 Ala Val Ile Ser Asn Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Phe                 85 90 95 Tyr Ser Gly Ser Tyr Tyr Tyr Pro Thr Asp Val His Glu Tyr Asp Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 284 <211> 130 <212> PRT <213> Lama Glama <400> 284 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Arg Gly Gly Ser Thr Tyr Tyr Glu Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Ile His Asn Cys Tyr Ser Gly Arg Tyr Tyr Ala Ser             100 105 110 Pro Asp Ala Val Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val         115 120 125 Ser Ser     130 <210> 285 <211> 125 <212> PRT <213> Lama Glama <400> 285 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Phe Thr Leu Asp His Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Gly Ser Thr Gly Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Lys Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Ser Tyr Tyr Ser Asp Leu Cys Gly Val Asn Gly Tyr             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 286 <211> 123 <212> PRT <213> Lama Glama <400> 286 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ser Tyr             20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val         35 40 45 Ala Val Ile Ser Ser Gly Asp Ser Thr Asn Tyr Ala Asp Ser Val Lys     50 55 60 Gly Arg Phe Thr Met Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Phe                 85 90 95 Tyr Ser Gly Ser Tyr Tyr Tyr Pro Ser Asp Val His Glu Tyr Asp Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 287 <211> 125 <212> PRT <213> Lama Glama <400> 287 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Gly Ser Thr Asp Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Ser Tyr Tyr Ser Gly Leu Cys Gly Val Asn Gly Val             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 288 <211> 120 <212> PRT <213> Lama Glama <400> 288 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Gly Val Tyr             20 25 30 Ala Thr Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Ser Gly Ser Asp Gly Ser Thr Trp Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Pro Lys Ser Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Leu Ser Leu Gly Ser Ser Trp Cys Ala Tyr Asp Tyr Trp Gly Gln             100 105 110 Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 289 <211> 130 <212> PRT <213> Lama Glama <400> 289 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Gly Arg Gly Gly Ser Thr Tyr Tyr Thr Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Val His Asn Cys Tyr Ser Gly Arg Tyr Tyr Ala Ser             100 105 110 Pro Asp Ala Val Tyr Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr Val         115 120 125 Ser Ser     130 <210> 290 <211> 123 <212> PRT <213> Lama Glama <400> 290 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ser Tyr             20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val         35 40 45 Ala Val Ile Ser Asn Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Ile Cys Phe                 85 90 95 Tyr Ser Gly Ser Tyr Tyr Tyr Pro Thr Asp Val His Glu Tyr Ala Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 291 <211> 125 <212> PRT <213> Lama Glama <400> 291 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr His             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Ser Ser Ser Gly Gly Ser Thr Ala Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Ser His Tyr Asn Asp Leu Cys Gly Val Asn Ala Ile             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 292 <211> 130 <212> PRT <213> Lama Glama <400> 292 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Arg Gly Ala Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Ile His Asn Cys Tyr Ser Gly Asn Gly Tyr Asp Ser             100 105 110 Pro Glu Ala Val Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val         115 120 125 Ser Ser     130 <210> 293 <211> 125 <212> PRT <213> Lama Glama <400> 293 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu His Tyr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Asn Ser Ser Asp Gly Ser Thr His Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Glu Tyr Tyr Ser Asp Leu Cys Gly Val Asn Gly Tyr             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 294 <211> 125 <212> PRT <213> Lama Glama <400> 294 Lys Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Asn Ser Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Glu Tyr Tyr Ser Asn Leu Cys Gly Val Asn Gly Tyr             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 295 <211> 130 <212> PRT <213> Lama Glama <400> 295 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Lys Tyr             20 25 30 Ser Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Ser Gly Gly Ser Thr Tyr Tyr Val Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Leu His Asn Cys Tyr Ser Gly Arg Gly Tyr Tyr Ser             100 105 110 Pro Glu Ala Val Tyr Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr Val         115 120 125 Ser Ser     130 <210> 296 <211> 130 <212> PRT <213> Lama Glama <400> 296 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Arg Gly Gly Ser Thr Tyr Tyr Thr Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Pro Ile His Asn Cys Tyr Ser Gly Ser Tyr Tyr Ala Ser             100 105 110 Pro Glu Ala Val Tyr Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr Val         115 120 125 Ser Ser     130 <210> 297 <211> 125 <212> PRT <213> Lama Glama <400> 297 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr             20 25 30 Asn Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val         35 40 45 Ser Cys Ile Asn Ser Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Phe Glu Tyr Tyr Ser Asn Leu Cys Gly Val Asn Gly Tyr             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 298 <211> 120 <212> PRT <213> Lama Glama <400> 298 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Pro Glu Gly Ile         35 40 45 Ser Cys Ile Ser Ser Ser Gly Ser Ile Thr Tyr Asp Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr Trp Gly Gln             100 105 110 Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 299 <211> 120 <212> PRT <213> Lama Glama <400> 299 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Pro Glu Gly Ile         35 40 45 Ser Cys Ile Ser Ser Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr Thr Gly Gln             100 105 110 Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 300 <211> 120 <212> PRT <213> Lama Glama <400> 300 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Pro Glu Gly Ile         35 40 45 Ser Cys Ile Ser Ser Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Thr Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr Thr Gly Gln             100 105 110 Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 301 <211> 120 <212> PRT <213> Lama Glama <400> 301 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Asp Val Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Pro Glu Gly Ile         35 40 45 Ser Cys Ile Ser Ser Ser Gly Ser Ile Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Thr Ser Arg Asp Ser Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr Trp Gly Gln             100 105 110 Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 302 <211> 120 <212> PRT <213> Lama Glama <400> 302 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Pro Glu Glu Ile         35 40 45 Ser Cys Ile Ser Ser Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr Thr Gly Gln             100 105 110 Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 303 <211> 126 <212> PRT <213> Lama Glama <400> 303 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Thr Ser Glu Arg Thr Val Ser Arg Tyr             20 25 30 Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Ala Val         35 40 45 Ala Thr Ile Ser Trp Ser Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Ile Asp Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Val Ala Lys Pro Asn Leu Lys Tyr Gly Ser Tyr Trp Pro Pro Arg Gly             100 105 110 Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 304 <211> 126 <212> PRT <213> Lama Glama <400> 304 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Thr Ser Glu Arg Thr Val Ser Arg Tyr             20 25 30 Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Ala Val         35 40 45 Ala Thr Ile Ser Trp Ser Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Lys Asn Met Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Val Ala Lys Pro Asn Leu Lys Tyr Gly Ser Thr Trp Pro Pro Arg Gly             100 105 110 Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 305 <211> 126 <212> PRT <213> Lama Glama <400> 305 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Thr Ser Glu Arg Ala Val Ser Arg Tyr             20 25 30 Thr Met Gly Trp Leu Arg Gln Ala Pro Gly Lys Glu Arg Glu Ala Val         35 40 45 Ala Thr Ile Ser Trp Ser Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Asp Tyr Tyr Cys                 85 90 95 Ala Ala Lys Pro Asn Leu Lys Tyr Gly Ser Tyr Trp Pro Pro Arg Gly             100 105 110 Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 306 <211> 126 <212> PRT <213> Lama Glama <400> 306 Glu Val Gln Leu Val Lys Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Thr Ser Glu Arg Thr Val Ser Arg Tyr             20 25 30 Gly Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Ala Val         35 40 45 Ala Thr Ile Ser Trp Ser Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Lys Pro Asn Leu Lys Tyr Gly Ser Asp Trp Pro Pro Arg Gly             100 105 110 Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 307 <211> 117 <212> PRT <213> Lama Glama <400> 307 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Ser Phe Ile Asn Lys Asp Gly Ser Asp Thr Gly Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Met Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Phe Cys                 85 90 95 Glu Thr Arg Thr Ser Arg Ser Pro Arg Pro Arg Gly Gln Gly Thr Gln             100 105 110 Val Thr Val Ser Ser         115 <210> 308 <211> 124 <212> PRT <213> Lama Glama <400> 308 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Arg Tyr             20 25 30 Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val         35 40 45 Ala Ala Ile Asn Trp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Asp Cys                 85 90 95 Ala Ala Ser Asn Tyr Tyr Ser Val Tyr Asp Asp Arg Pro Val Met Asp             100 105 110 Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 309 <211> 116 <212> PRT <213> Lama Glama <400> 309 Glu Val Gln Leu Met Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ala Gly Phe Thr Phe Ser Asn Tyr             20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Ser Val Ile Ser Pro Asp Gly Ser Asn Thr Tyr Tyr Ala Asp Thr Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Gly Asn Ala Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Thr Gly Leu Lys Ser Glu Asp Ala Ala Val Tyr Tyr Cys                 85 90 95 Ala Arg Gly Ser Gly Ser Trp Gly Val His Gly Gln Gly Thr Gln Val             100 105 110 Thr Val Ser Ser         115 <210> 310 <211> 128 <212> PRT <213> Lama Glama <400> 310 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asn Tyr             20 25 30 Ile Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val         35 40 45 Ala Gly Ile Ser Arg Tyr Gly Asp Tyr Thr Ala Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Lys Asn Thr Val Tyr 65 70 75 80 Leu Arg Met Asn Ser Leu Lys Pro Asp Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asn Glu Gly Tyr Cys Ser Gly Tyr Gly Cys Tyr Glu Asp Ser             100 105 110 Gly Gln Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 311 <211> 128 <212> PRT <213> Lama Glama <400> 311 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asn Tyr             20 25 30 Ile Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val         35 40 45 Ala Gly Ile Ser Arg Tyr Gly Asp Tyr Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Lys Asn Thr Val Tyr 65 70 75 80 Leu Arg Met Asn Ser Leu Lys Pro Asp Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asn Glu Gly Tyr Cys Ser Gly Tyr Gly Cys Tyr Glu Asp Ser             100 105 110 Gly Gln Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 312 <211> 121 <212> PRT <213> Lama Glama <400> 312 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Thr Thr Tyr             20 25 30 Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val         35 40 45 Ala Ala Val Ser Arg Phe Gly Val Ser Trp Asp Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Ala Asn Thr Leu Lys 65 70 75 80 Leu Arg Met Asn Ser Leu Lys Ala Asp Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Gly Gly Arg Ser Phe Leu Pro Phe Val Pro Ala Tyr Trp Gly             100 105 110 Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 313 <211> 128 <212> PRT <213> Lama Glama <400> 313 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asn Tyr             20 25 30 Ile Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val         35 40 45 Ala Gly Ile Ser Arg Tyr Ala Asp Tyr Thr Gly Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Lys Asn Thr Val Tyr 65 70 75 80 Leu Arg Met Asn Ser Leu Lys Pro Asp Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asn Glu Gly Tyr Cys Ser Gly Tyr Gly Cys Tyr Glu Asp Ser             100 105 110 Gly Gln Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 314 <211> 126 <212> PRT <213> Lama Glama <400> 314 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Tyr Ile Met             20 25 30 Gly Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Gly         35 40 45 Ile Ser Arg Tyr Gly Asp Ile Thr Tyr Ala Ala Asp Ser Val Lys Gly     50 55 60 Arg Phe Thr Ile Ser Arg Asp Ser Val Lys Asn Thr Val Tyr Leu Arg 65 70 75 80 Met Asn Ser Leu Lys Pro Asp Asp Thr Ala Val Tyr Tyr Cys Ala Ala                 85 90 95 Asn Gly Gly Tyr Cys Ser Gly Tyr Gly Cys Tyr Glu Asp Ser Gly Gln             100 105 110 Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 315 <211> 120 <212> PRT <213> Lama Glama <400> 315 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Pro Glu Gly Ile         35 40 45 Ser Cys Ile Ser Ser Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr Thr Gly Gln             100 105 110 Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 316 <211> 120 <212> PRT <213> Lama Glama <400> 316 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Pro Glu Glu Ile         35 40 45 Ser Cys Ile Ser Ser Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr Thr Gly Gln             100 105 110 Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 317 <211> 120 <212> PRT <213> Lama Glama <400> 317 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Pro Glu Gly Ile         35 40 45 Ser Cys Ile Ser Ser Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr Thr Gly Gln             100 105 110 Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 318 <211> 123 <212> PRT <213> Lama Glama <400> 318 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ile Pro Arg Gly Trp Gly Pro Thr Gly Pro Ile Glu Tyr Ala Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 319 <211> 123 <212> PRT <213> Lama Glama <400> 319 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ile Pro Arg Gly Trp Gly Pro Thr Gly Pro Ile Glu Tyr Gly Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 320 <211> 123 <212> PRT <213> Lama Glama <400> 320 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Ser Cys                 85 90 95 Ala Ile Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Gly Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 321 <211> 123 <212> PRT <213> Lama Glama <400> 321 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ser Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ile Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Ala Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 322 <211> 121 <212> PRT <213> Lama Glama <400> 322 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val         35 40 45 Ala Ala Ile Asn Trp Ser Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Pro Ala Pro Gly Ser Ser Gly Tyr Glu Tyr Asp Tyr Trp Gly             100 105 110 Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 323 <211> 120 <212> PRT <213> Lama Glama <400> 323 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Asp Val Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Pro Glu Gly Ile         35 40 45 Ser Cys Ile Ser Ser Ser Gly Ser Ile Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr Trp Gly Gln             100 105 110 Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 324 <211> 123 <212> PRT <213> Lama Glama <400> 324 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr             20 25 30 Asp Met Ser Trp Val Arg His Ala Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Thr Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ile Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Ala Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 325 <211> 123 <212> PRT <213> Lama Glama <400> 325 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Thr Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ile Pro Arg Gly Trp Gly Pro Thr Gly Pro Leu Glu Tyr Gly Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 326 <211> 123 <212> PRT <213> Lama Glama <400> 326 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr             20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Asp Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Gly Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 327 <211> 123 <212> PRT <213> Lama Glama <400> 327 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr             20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Asn Leu Gln Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Gly Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 328 <211> 123 <212> PRT <213> Lama Glama <400> 328 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ile Thr Tyr Tyr Ala Asp Leu Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ile Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Gly Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 329 <211> 123 <212> PRT <213> Lama Glama <400> 329 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Tyr             20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Gly Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 330 <211> 123 <212> PRT <213> Lama Glama <400> 330 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Thr Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ile Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Ala Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 331 <211> 123 <212> PRT <213> Lama Glama <400> 331 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Gly Asn Tyr             20 25 30 Asp Met Ser Trp Val Arg Arg Pro Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Gly Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 332 <211> 123 <212> PRT <213> Lama Glama <400> 332 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Ser Cys                 85 90 95 Ala Ile Pro Arg Gly Trp Gly Pro Thr Gly Pro His Glu Tyr Ala Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 333 <211> 14 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 333 Arg Ala Pro Asp Thr Arg Leu Arg Pro Tyr Leu Tyr Asp Tyr 1 5 10 <210> 334 <211> 14 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 334 Arg Ala Pro Asp Thr Arg Leu Glu Pro Tyr Glu Tyr Asp His 1 5 10 <210> 335 <211> 14 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 335 Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr Glu Tyr Asp His 1 5 10 <210> 336 <211> 14 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 336 Arg Ala Pro Asp Thr Arg Leu Glu Pro Tyr Leu Tyr Asp His 1 5 10 <210> 337 <211> 14 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 337 Arg Ala Pro Asp Thr Arg Leu Glu Pro Tyr Leu Tyr Asp Tyr 1 5 10 <210> 338 <211> 14 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 338 Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr Leu Tyr Asp Tyr 1 5 10 <210> 339 <211> 14 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 339 Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr Glu Tyr Asp His 1 5 10 <210> 340 <211> 14 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 340 Arg Ala Pro Asp Thr Arg Leu Arg Pro Tyr Leu Tyr Asp Tyr 1 5 10 <210> 341 <211> 14 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 341 Arg Ala Pro Asp Thr Arg Leu Glu Pro Tyr Leu Tyr Asp His 1 5 10 <210> 342 <211> 14 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 342 Arg Ala Pro Asp Thr Arg Leu Glu Pro Tyr Glu Tyr Asp His 1 5 10 <210> 343 <211> 14 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 343 Arg Ala Pro Asp Thr Arg Leu Arg Pro Tyr Glu Tyr Asp Tyr 1 5 10 <210> 344 <211> 14 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 344 Arg Ala Pro Asp Thr Arg Leu Glu Pro Tyr Leu Tyr Asp His 1 5 10 <210> 345 <211> 14 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 345 Arg Ala Pro Asp Thr Arg Leu Gly Pro Tyr Leu Tyr Asp Tyr 1 5 10 <210> 346 <211> 14 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 346 Arg Ala Pro Asp Thr Arg Leu Glu Pro Tyr Glu Tyr Asp Tyr 1 5 10 <210> 347 <211> 14 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 347 Arg Ala Pro Asp Thr Arg Leu Gly Pro Tyr Leu Tyr Asp His 1 5 10 <210> 348 <211> 14 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 348 Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr Leu Tyr Asp His 1 5 10 <210> 349 <211> 14 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 349 Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr Leu Tyr Asp Tyr 1 5 10 <210> 350 <211> 14 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 350 Arg Ala Pro Asp Thr Arg Leu Arg Pro Tyr Leu Tyr Asp His 1 5 10 <210> 351 <211> 14 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 351 Arg Ala Pro Asp Thr Arg Leu Glu Pro Tyr Leu Tyr Asp His 1 5 10 <210> 352 <211> 14 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 352 Arg Ala Pro Asp Thr Arg Leu Glu Pro Tyr Glu Tyr Asp His 1 5 10 <210> 353 <211> 14 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 353 Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr Glu Tyr Asp Tyr 1 5 10 <210> 354 <211> 123 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 354 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Arg Pro Tyr Leu Tyr Asp Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 355 <211> 123 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 355 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Glu Pro Tyr Glu Tyr Asp His             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 356 <211> 123 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 356 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr Glu Tyr Asp His             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 357 <211> 123 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 357 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Gln Ser Arg Phe Thr Ile Thr Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Glu Pro Tyr Leu Tyr Asp His             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 358 <211> 123 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 358 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Glu Pro Tyr Leu Tyr Asp Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 359 <211> 123 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 359 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Asp Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr Leu Tyr Asp Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 360 <211> 123 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 360 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Pro Asp Ser Val     50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr Glu Tyr Asp His             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 361 <211> 123 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 361 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Arg Pro Tyr Leu Tyr Asp Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 362 <211> 123 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 362 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Glu Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Glu Pro Tyr Leu Tyr Asp His             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 363 <211> 123 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 363 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Gln Ser Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Glu Pro Tyr Glu Tyr Asp His             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 364 <211> 123 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 364 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Arg Pro Tyr Glu Tyr Asp Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 365 <211> 123 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 365 Glu Val Gln Leu Val Glu Ser Arg Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Glu Pro Tyr Leu Tyr Asp His             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 366 <211> 123 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 366 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Leu Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Gly Pro Tyr Leu Tyr Asp Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 367 <211> 123 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 367 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Glu Pro Tyr Glu Tyr Asp Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 368 <211> 123 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 368 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Gly Pro Tyr Leu Tyr Asp His             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 369 <211> 123 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 369 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Tyr Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr Leu Tyr Asp His             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 370 <211> 123 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 370 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr Leu Tyr Asp Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 371 <211> 123 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 371 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Arg Pro Tyr Leu Tyr Asp His             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 372 <211> 123 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 372 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Glu Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Glu Pro Tyr Leu Tyr Asp His             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 373 <211> 123 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 373 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Glu Pro Tyr Glu Tyr Asp His             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 374 <211> 123 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 374 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr Glu Tyr Asp Tyr             100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 375 <211> 19 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 375 Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala Tyr Gln 1 5 10 15 Tyr Asp Tyr              <210> 376 <211> 19 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 376 Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala Tyr Ala 1 5 10 15 Tyr Asp Tyr              <210> 377 <211> 19 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 377 Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala Tyr Val 1 5 10 15 Tyr Asp Tyr              <210> 378 <211> 19 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 378 Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala Tyr Gln 1 5 10 15 Tyr Asp Tyr              <210> 379 <211> 19 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 379 Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala Tyr Val 1 5 10 15 Tyr Asp Tyr              <210> 380 <211> 19 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 380 Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala Tyr Gln 1 5 10 15 Tyr Asp Tyr              <210> 381 <211> 19 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 381 Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala Tyr Ala 1 5 10 15 Tyr Asp Tyr              <210> 382 <211> 19 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 382 Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala Tyr Ala 1 5 10 15 Tyr Asp Tyr              <210> 383 <211> 19 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 383 Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala Tyr Ala 1 5 10 15 Tyr Asp Tyr              <210> 384 <211> 19 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 384 Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala Tyr Ala 1 5 10 15 Tyr Asp Tyr              <210> 385 <211> 19 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 385 Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala Tyr Gln 1 5 10 15 Tyr Asp Tyr              <210> 386 <211> 19 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 386 Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala Tyr Glu 1 5 10 15 Tyr Asp Tyr              <210> 387 <211> 19 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 387 Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala Tyr Ala 1 5 10 15 Tyr Asp Tyr              <210> 388 <211> 19 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 388 Asp Arg Tyr Ile Trp Ala Arg Gln Gly Asp Tyr Trp Gly Ala Tyr Val 1 5 10 15 Tyr Asp Tyr              <210> 389 <211> 19 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 389 Asp Arg Tyr Ile Trp Ala Arg Gln Gly Asp Tyr Trp Gly Ala Tyr Ala 1 5 10 15 Tyr Asp Tyr              <210> 390 <211> 19 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 390 Asp Arg Tyr Ile Arg Ala Arg Gln Gly Glu Tyr Trp Gly Ala Tyr Ala 1 5 10 15 Tyr Asp Tyr              <210> 391 <211> 19 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 391 Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala Tyr Ala 1 5 10 15 Tyr Asp Tyr              <210> 392 <211> 19 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 392 Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala Tyr Glu 1 5 10 15 Tyr Asp Tyr              <210> 393 <211> 19 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 393 Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala Tyr Ala 1 5 10 15 Tyr Asp Tyr              <210> 394 <211> 19 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 394 Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala Tyr Gln 1 5 10 15 Tyr Asp Tyr              <210> 395 <211> 19 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 395 Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala Tyr Ala 1 5 10 15 Tyr Asp Tyr              <210> 396 <211> 128 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 396 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Arg Ser Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Phe Tyr Thr Asp Tyr Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala             100 105 110 Tyr Gln Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 397 <211> 128 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 397 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Arg Ser Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Tyr Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala             100 105 110 Tyr Ala Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 398 <211> 128 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 398 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Arg Ser Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Thr Asp Tyr Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala             100 105 110 Tyr Val Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 399 <211> 128 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 399 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Arg Ser Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Tyr Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala             100 105 110 Tyr Gln Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 400 <211> 128 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 400 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Arg Ser Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Thr Asp Tyr Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala             100 105 110 Tyr Val Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 401 <211> 128 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 401 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Arg Ser Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Thr Asp Tyr Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala             100 105 110 Tyr Gln Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 402 <211> 128 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 402 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Arg Ser Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Thr Asp Tyr Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala             100 105 110 Tyr Ala Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 403 <211> 128 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 403 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Arg Ser Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Thr Asp Tyr Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala             100 105 110 Tyr Ala Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 404 <211> 128 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 404 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Arg Ser Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Thr Asp Phe Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala             100 105 110 Tyr Ala Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 405 <211> 128 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 405 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Arg Ser Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ser Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Thr Asp Tyr Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala             100 105 110 Tyr Ala Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 406 <211> 128 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 406 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Arg Ser Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Tyr Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala             100 105 110 Tyr Gln Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 407 <211> 128 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 407 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Arg Ser Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ser Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Tyr Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala             100 105 110 Tyr Glu Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 408 <211> 128 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 408 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Arg Ser Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Asp Ser Thr Phe Tyr Ala Asp Tyr Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala             100 105 110 Tyr Ala Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 409 <211> 128 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 409 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr             20 25 30 Asp Met Ser Trp Leu Arg Arg Ser Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Tyr Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Arg Tyr Ile Trp Ala Arg Gln Gly Asp Tyr Trp Gly Ala             100 105 110 Tyr Val Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 410 <211> 128 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 410 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Arg Ser Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Thr Asp Tyr Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Arg Tyr Ile Trp Ala Arg Gln Gly Asp Tyr Trp Gly Ala             100 105 110 Tyr Ala Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 411 <211> 128 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 411 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Arg Ser Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Thr Asp Tyr Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Arg Tyr Ile Arg Ala Arg Gln Gly Glu Tyr Trp Gly Ala             100 105 110 Tyr Ala Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 412 <211> 128 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence &Lt; 400 > 412 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Arg Ser Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ser Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Thr Asp Phe Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala             100 105 110 Tyr Ala Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 413 <211> 128 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 413 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Arg Ser Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Thr Asp Tyr Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala             100 105 110 Tyr Glu Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 414 <211> 128 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 414 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Arg Ser Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ser Ile Asn Ser Gly Gly Gly Ser Thr Phe Tyr Thr Asp Phe Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala             100 105 110 Tyr Ala Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 415 <211> 128 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 415 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Arg Ser Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Thr Asp Tyr Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala             100 105 110 Tyr Gln Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 416 <211> 128 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 416 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Gly Ser Tyr             20 25 30 Asp Met Ser Trp Val Arg Arg Ser Pro Gly Lys Gly Pro Glu Trp Val         35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Tyr Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Asp Arg Tyr Ile Trp Ala Arg Gln Gly Glu Tyr Trp Gly Ala             100 105 110 Tyr Ala Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 417 <211> 687 <212> PRT <213> Homo sapiens <400> 417 His Met Met Ala Ala Ala Ser Arg Ser Ala Ser Gly Trp Ala Leu Leu 1 5 10 15 Leu Leu Val Ala Leu Trp Gln Gln Arg Ala Ala Gly Ser Gly Val Phe             20 25 30 Gln Leu Gln Leu Gln Glu Phe Ile Asn Glu Arg Gly Val Leu Ala Ser         35 40 45 Gly Arg Pro Cys Glu Pro Gly Cys Arg Thr Phe Phe Arg Val Cys Leu     50 55 60 Lys His Phe Gln Ala Val Val Ser Pro Gly Pro Cys Thr Phe Gly Thr 65 70 75 80 Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe Ala Val Arg Asp Asp                 85 90 95 Ser Ser Gly Gly Gly Arg Asn Pro Leu Gln Leu Pro Phe Asn Phe Thr             100 105 110 Trp Pro Gly Thr Phe Ser Leu Ile Ile Glu Ala Trp His Ala Pro Gly         115 120 125 Asp Asp Leu Arg Pro Glu Ala Leu Pro Pro Asp Ala Leu Ile Ser Lys     130 135 140 Ile Ala Ile Gln Gly Ser Leu Ala Val Gly Gln Asn Trp Leu Leu Asp 145 150 155 160 Glu Gln Thr Ser Thr Leu Thr Arg Leu Arg Tyr Ser Tyr Arg Val Ile                 165 170 175 Cys Ser Asp Asn Tyr Tyr Gly Asp Asn Cys Ser Arg Leu Cys Lys Lys             180 185 190 Arg Asn Asp His Phe Gly His Tyr Val Cys Gln Pro Asp Gly Asn Leu         195 200 205 Ser Cys Leu Pro Gly Trp Thr Gly Glu Tyr Cys Gln Gln Pro Ile Cys     210 215 220 Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys Ser Lys Pro Ala Glu 225 230 235 240 Cys Leu Cys Arg Pro Gly Trp Gln Gly Arg Leu Cys Asn Glu Cys Ile                 245 250 255 Pro His Asn Gly Cys Arg His Gly Thr Cys Ser Thr Pro Trp Gln Cys             260 265 270 Thr Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys Asp Gln Asp Leu Asn         275 280 285 Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly Ala Thr Cys Ser Asn     290 295 300 Ser Gly Gln Arg Ser Tyr Thr Cys Thr Cys Arg Pro Gly Tyr Thr Gly 305 310 315 320 Val Asp Cys Glu Leu Glu Leu Ser Glu Cys Asp Ser Asn Pro Cys Arg                 325 330 335 Asn Gly Gly Ser Cys Lys Asp Gln Glu Asp Gly Tyr His Cys Leu Cys             340 345 350 Pro Pro Gly Tyr Tyr Gly Leu His Cys Glu His Ser Thr Leu Ser Cys         355 360 365 Ala Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg Glu Arg Asn Gln     370 375 380 Gly Ala Asn Tyr Ala Cys Glu Cys Pro Pro Asn Phe Thr Gly Ser Asn 385 390 395 400 Cys Glu Lys Lys Val Asp Arg Cys Thr Ser Asn Pro Cys Ala Asn Gly                 405 410 415 Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg Met Cys Arg Cys Arg Pro             420 425 430 Gly Phe Thr Gly Thr Tyr Cys Glu Leu His Val Ser Asp Cys Ala Arg         435 440 445 Asn Pro Cys Ala His Gly Gly Thr Cys His Asp Leu Glu Asn Gly Leu     450 455 460 Met Cys Thr Cys Pro Ala Gly Phe Ser Gly Arg Arg Cys Glu Val Arg 465 470 475 480 Thr Ser Ile Asp Ala Cys Ala Ser Ser Pro Cys Phe Asn Arg Ala Thr                 485 490 495 Cys Tyr Thr Asp Leu Ser Thr Asp Thr Phe Val Cys Asn Cys Pro Tyr             500 505 510 Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val Gly Leu Pro Pro Ser         515 520 525 Phe Pro Trp Val Ala Val Ser Leu Gly Val Gly Leu Ala Val Leu Leu     530 535 540 Val Leu Leu Gly Met Val Ala Val Ala Val Arg Gln Leu Arg Leu Arg 545 550 555 560 Arg Pro Asp Asp Gly Ser Arg Glu Ala Met Asn Asn Leu Ser Asp Phe                 565 570 575 Gln Lys Asp Asn Leu Ile Pro Ala Ala Gln Leu Lys Asn Thr Asn Gln             580 585 590 Lys Lys Glu Leu Glu Val Asp Cys Gly Leu Asp Lys Ser Asn Cys Gly         595 600 605 Lys Gln Gln Asn His Thr Leu Asp Tyr Asn Leu Ala Pro Gly Pro Leu     610 615 620 Gly Arg Gly Thr Met Pro Gly Lys Phe Pro His Ser Asp Lys Ser Leu 625 630 635 640 Gly Glu Lys Ala Pro Leu Arg Leu His Ser Glu Lys Pro Glu Cys Arg                 645 650 655 Ile Ser Ala Ile Cys Ser Pro Arg Asp Ser Met Tyr Gln Ser Val Cys             660 665 670 Leu Ile Ser Glu Glu Arg Asn Glu Cys Val Ile Ala Thr Glu Val         675 680 685 <210> 418 <211> 707 <212> PRT <213> Macaca mulatta <400> 418 Met Ala Cys Ala Cys Ala Met Leu Ala Thr Thr Ala Arg His Glu Ser 1 5 10 15 Ser Met Asn Lys Glu Tyr Met Ala Ala Ala Ser Trp Ser Ala Ser Gly             20 25 30 Trp Ala Leu Leu Leu Leu Val Ala Leu Trp Gln Gln Arg Ala Ala Gly         35 40 45 Ser Gly Val Phe Gln Leu Gln Leu Gln Glu Phe Val Asn Glu Arg Gly     50 55 60 Val Leu Ala Ser Gly Arg Pro Cys Glu Pro Gly Cys Arg Thr Phe Phe 65 70 75 80 Arg Val Cys Leu Lys His Phe Gln Ala Val Val Ser Pro Gly Pro Cys                 85 90 95 Thr Phe Gly Ser Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe Ala             100 105 110 Val Arg Asp Asp Ser Ser Gly Gly Gly Arg Asn Pro Leu Gln Leu Pro         115 120 125 Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu Ile Glu Ala Trp     130 135 140 His Ala Pro Gly Asp Asp Leu Arg Pro Glu Ala Leu Pro Pro Asp Ala 145 150 155 160 Leu Ile Ser Lys Ile Ala Ile Gln Gly Ser Leu Ala Val Gly Gln Asn                 165 170 175 Trp Leu Leu Asp Glu Gln Thr Ser Thr Leu Thr Arg Leu Arg Tyr Ser             180 185 190 Tyr Arg Val Ile Cys Ser Asp Asn Tyr Tyr Gly Asp Asn Cys Ser Arg         195 200 205 Leu Cys Lys Lys Arg Asn Asp His Phe Gly His Tyr Val Cys Gln Pro     210 215 220 Asp Gly Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu Tyr Cys Gln 225 230 235 240 Gln Pro Ile Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys Ser                 245 250 255 Lys Pro Ala Glu Cys Leu Cys Arg Pro Gly Trp Gln Gly Arg Leu Cys             260 265 270 Asn Glu Cys Ile Pro His Asn Gly Cys Arg His Gly Thr Cys Ser Thr         275 280 285 Pro Trp Gln Cys Thr Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys Asp     290 295 300 Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly Ala 305 310 315 320 Thr Cys Ser Asn Ser Gly Gln Arg Ser Tyr Thr Cys Thr Cys Arg Pro                 325 330 335 Gly Tyr Thr Gly Val Asp Cys Glu Leu Glu Leu Ser Glu Cys Asp Ser             340 345 350 Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asp Gly Tyr         355 360 365 His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys Glu His Ser     370 375 380 Thr Leu Ser Cys Ala Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg 385 390 395 400 Glu Arg Asn Gln Gly Ala Ser Tyr Ala Cys Glu Cys Pro Pro Asn Phe                 405 410 415 Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser Asn Pro             420 425 430 Cys Ala Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg Met Cys         435 440 445 Arg Cys Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Arg His Val Ser     450 455 460 Asp Cys Ala Arg Asn Pro Cys Ala His Gly Gly Thr Cys His Asp Leu 465 470 475 480 Glu Ser Gly Leu Met Cys Thr Cys Pro Ala Gly Phe Ser Gly Arg Arg                 485 490 495 Cys Glu Val Arg Thr Ser Ile Asp Ala Cys Ala Ser Ser Pro Cys Phe             500 505 510 Asn Arg Ala Thr Cys Tyr Thr Asp Leu Ser Thr Asp Thr Phe Val Cys         515 520 525 Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val Gly     530 535 540 Leu Pro Pro Ser Phe Pro Trp Val Ala Val Ser Leu Gly Val Gly Leu 545 550 555 560 Ala Val Leu Leu Val Leu Leu Gly Met Val Ala Val Ala Val Arg Gln                 565 570 575 Leu Arg Leu Arg Arg Pro Asp Asp Gly Ser Arg Glu Ala Met Asn Asn             580 585 590 Leu Ser Asp Phe Gln Lys Asp Asn Leu Ile Pro Ala Ala Gln Leu Lys         595 600 605 Asn Thr Asn Gln Lys Lys Glu Leu Glu Val Asp Cys Gly Leu Asp Lys     610 615 620 Ser Asn Cys Gly Lys Gln Gln Asn His Thr Leu Asp Tyr Asn Leu Ala 625 630 635 640 Pro Gly Pro Leu Gly Arg Gly Thr Met Pro Gly Lys Phe Pro His Ser                 645 650 655 Asp Lys Ser Leu Gly Glu Lys Ala Pro Leu Arg Leu His Ser Glu Lys             660 665 670 Pro Glu Cys Arg Ile Ser Ala Ile Cys Ser Pro Arg Asp Ser Met Tyr         675 680 685 Gln Ser Val Cys Leu Ile Ser Glu Glu Arg Asn Glu Cys Val Ile Ala     690 695 700 Thr Glu Val 705 <210> 419 <211> 472 <212> PRT <213> Homo sapiens <400> 419 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Asn             20 25 30 Trp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Tyr Ile Ser Pro Asn Ser Gly Phe Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Arg Asp Asn Phe Gly Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr             100 105 110 Leu Val Thr Val Ser Ser Gly Glu Trp Ile Leu Cys Ala Trp Ala Gln         115 120 125 Leu Cys Pro Thr Pro Arg Ser His Gly Thr Thr Ser Leu Ala Ala Ser     130 135 140 Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr 145 150 155 160 Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro                 165 170 175 Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val             180 185 190 His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser         195 200 205 Ser Val Val Thr Val Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile     210 215 220 Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val 225 230 235 240 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala                 245 250 255 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro             260 265 270 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val         275 280 285 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val     290 295 300 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 305 310 315 320 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln                 325 330 335 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala             340 345 350 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro         355 360 365 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr     370 375 380 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 385 390 395 400 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr                 405 410 415 Lys Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr             420 425 430 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe         435 440 445 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys     450 455 460 Ser Leu Ser Leu Ser Pro Gly Lys 465 470 <210> 420 <211> 115 <212> PRT <213> Homo sapiens <400> 420 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala             20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile         35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Ser Ser Phe Ser Gly     50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Thr Tyr Tyr Cys Gln Gln Ser Tyr Thr Gly Thr                 85 90 95 Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Trp Ile             100 105 110 His Leu Gly         115 <210> 421 <211> 21 <212> DNA <213> Artificial <220> <223> Primer <400> 421 gcgaacagag ccagattgag g 21 <210> 422 <211> 21 <212> DNA <213> Artificial <220> <223> Primer <400> 422 ggatgtccag gtaggctcct g 21 <210> 423 <211> 20 <212> DNA <213> Artificial <220> <223> Primer <400> 423 gagcgacatc cctaacaagc 20 <210> 424 <211> 20 <212> DNA <213> Artificial <220> <223> Primer <400> 424 cctcaactct gttcccttgg 20 <210> 425 <211> 21 <212> DNA <213> Artificial <220> <223> Primer <400> 425 gcgaacagag ccagattcag g 21 <210> 426 <211> 20 <212> DNA <213> Artificial <220> <223> Primer <400> 426 ccagacagac acccaaaggt 20 <210> 427 <211> 45 <212> DNA <213> Artificial <220> <223> Primer <400> 427 gaggtgcaat tggtggagtc tgggggtggt ctggttcagg ctggt 45 <210> 428 <211> 45 <212> DNA <213> Artificial <220> <223> Primer <400> 428 tcctgcgcag cttctggtcg taccttctcc agctacgcga tggct 45 <210> 429 <211> 45 <212> DNA <213> Artificial <220> <223> Primer <400> 429 ccaggcaaag aacgcgagtw cgtagccgca atccgttgga gcggt 45 <210> 430 <211> 44 <212> DNA <213> Artificial <220> <223> Primer <400> 430 ctgattccgt tcagggtcgt ttcaccatct ctcgtgacaa cgcg 44 <210> 431 <211> 45 <212> DNA <213> Artificial <220> <223> Primer <400> 431 ctgcagatga actctctgaa accggaagat acggcagtct actac 45 <210> 432 <211> 46 <212> DNA <213> Artificial <220> <223> Primer <400> 432 gacactcgtc tgcgtccgta cctgtacgac yattggggtc agggta 46 <210> 433 <211> 46 <212> DNA <213> Artificial <220> <223> Primer <400> 433 gacactcgtc tggvaccgta cctgtacgac yattggggtc agggta 46 <210> 434 <211> 46 <212> DNA <213> Artificial <220> <223> Primer <400> 434 gacactcgtc tgcgtccgta cgagtacgac yattggggtc agggta 46 <210> 435 <211> 46 <212> DNA <213> Artificial <220> <223> Primer <400> 435 gacactcgtc tggvaccgta cgagtacgac yattggggtc agggta 46 <210> 436 <211> 45 <212> DNA <213> Artificial <220> <223> Primer <400> 436 cagacgagtg tccggcgcac ggtttgcaca gtagtagact gccgt 45 <210> 437 <211> 45 <212> DNA <213> Artificial <220> <223> Primer <400> 437 cagacgagtg tctrccgcac ggtttgcaca gtagtagact gccgt 45 <210> 438 <211> 45 <212> DNA <213> Artificial <220> <223> Primer <400> 438 agagttcatc tgcagataga cggtgttttt cgcgttgtca cgaga 45 <210> 439 <211> 45 <212> DNA <213> Artificial <220> <223> Primer <400> 439 ctgaacggaa tcagsgtaat acgcagttyc accgctccaa cggat 45 <210> 440 <211> 45 <212> DNA <213> Artificial <220> <223> Primer &Lt; 400 > 440 gcgttctttg cctggagcct gacgawacca agccatcgcg tagct 45 <210> 441 <211> 45 <212> DNA <213> Artificial <220> <223> Primer <400> 441 agaagctgcg caggacagac ggagagagcc accagcctga accag 45 <210> 442 <211> 35 <212> DNA <213> Artificial <220> <223> Primer <400> 442 tgaggagacg gtgacctggg tcccctgacc ccaat 35 <210> 443 <211> 45 <212> DNA <213> Artificial <220> <223> Primer <400> 443 gaggtgcaat tggtggagtc tgggggtggt ctggttcagc caggt 45 <210> 444 <211> 32 <212> DNA <213> Artificial <220> <223> Primer <400> 444 tgaggagacg gtgacctggg tcccctgacc cc 32 <210> 445 <211> 45 <212> DNA <213> Artificial <220> <223> Primer <400> 445 gtgcagcttc cggctttacg wtcggctcct acgacatgtc ttggg 45 <210> 446 <211> 49 <212> DNA <213> Artificial <220> <223> Primer <400> 446 acgcacccca gtattcaccc tgacgcgccc aaatgtagcg atctgcagc 49 <210> 447 <211> 45 <212> DNA <213> Artificial <220> <223> Primer <400> 447 aggtccggaa tgggtgtcck ctatcaactc tggtggtggt agcac 45 <210> 448 <211> 45 <212> DNA <213> Artificial <220> <223> Primer <400> 448 tcttccggtt tcaggctgtt catctgcagg tacagcgtgt ttttg 45 <210> 449 <211> 45 <212> DNA <213> Artificial <220> <223> Primer <400> 449 aaaggtcgtt tcaccatctc tcgtgacaac gccaaaaaca cgctg 45 <210> 450 <211> 45 <212> DNA <213> Artificial <220> <223> Primer <400> 450 tgaaacgacc ttttwcgwag tcggygtagw aggtgctacc accac 45 <210> 451 <211> 45 <212> DNA <213> Artificial <220> <223> Primer <400> 451 tgaaaccgga agataccgcg gtatactact gcgctgcaga tcgct 45 <210> 452 <211> 45 <212> DNA <213> Artificial <220> <223> Primer <400> 452 ccattccgga cctttacccg gagaacgacg aacccaagac atgtc 45 <210> 453 <211> 41 <212> DNA <213> Artificial <220> <223> Primer <400> 453 tactggggtg cgtacghata cgactactgg ggtcagggta c 41 <210> 454 <211> 41 <212> DNA <213> Artificial <220> <223> Primer <400> 454 tactggggtg cgtaccagta cgactactgg ggtcagggta c 41 <210> 455 <211> 45 <212> DNA <213> Artificial <220> <223> Primer <400> 455 ccggaagctg cacagctcag acgcagagaa ccacctggct gaacc 45 <210> 456 <211> 49 <212> DNA <213> Artificial <220> <223> Primer <400> 456 acgcacccca gtagtaaccc tgacgcgccc raatgtagcg atctgcagc 49 <210> 457 <211> 49 <212> DNA <213> Artificial <220> <223> Primer <400> 457 acgcacccca gtaktcaccc tgacgcgccc raatgtagcg atctgcagc 49                          <210> 458 <211> 11 <212> PRT <213> Lama glama <400> 458 Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr 1 5 10 <210> 459 <211> 120 <212> PRT <213> Lama glama <400> 459 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Pro Glu Gly Ile         35 40 45 Ser Cys Ile Ser Ser Ser Gly Ser Ile Thr Tyr Asp Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Pro Gly Ile Ala Ala Cys Arg Gly Ile His Tyr Trp Gly Gln             100 105 110 Gly Thr Gln Val Thr Val Ser Ser         115 120                       <210> 460 <211> 513 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence &Lt; 400 > 460 Asp Val Gln Leu Val Glu Ser Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr Glu Tyr Asp His             100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser         115 120 125 Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val     130 135 140 Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ser Ser Gly Phe Thr 145 150 155 160 Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly                 165 170 175 Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr             180 185 190 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys         195 200 205 Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala     210 215 220 Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly 225 230 235 240 Thr Leu Val Thr Val Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Ser                 245 250 255 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly             260 265 270 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr         275 280 285 Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val     290 295 300 Ser Cys Ile Arg Cys Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val 305 310 315 320 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr                 325 330 335 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys             340 345 350 Ala Ala Ser Ile Val Pro Arg Ser Ser Lys Leu Glu Pro Tyr Glu Tyr Asp         355 360 365 Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly     370 375 380 Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu 385 390 395 400 Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ser Ser Gly Phe                 405 410 415 Thr Phe Asp Asp Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys             420 425 430 Glu Arg Glu Gly Val Ser Cys Ile Arg Cys Ser Asp Gly Ser Thr Tyr         435 440 445 Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser     450 455 460 Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr 465 470 475 480 Ala Val Tyr Tyr Cys Ala Ala Ser Ile Val Pro Arg Ser Lys Leu Glu                 485 490 495 Pro Tyr Glu Tyr Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser             500 505 510 Ser      <210> 461 <211> 513 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 461 Asp Val Gln Leu Val Glu Ser Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Arg Cys Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Ser Ile Val Pro Arg Ser Ser Lys Leu Glu Pro Tyr Glu Tyr Asp             100 105 110 Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly         115 120 125 Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu     130 135 140 Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ser Ser Gly Phe 145 150 155 160 Thr Phe Asp Asp Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys                 165 170 175 Glu Arg Glu Gly Val Ser Cys Ile Arg Cys Ser Asp Gly Ser Thr Tyr             180 185 190 Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser         195 200 205 Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr     210 215 220 Ala Val Tyr Tyr Cys Ala Ala Ser Ile Val Pro Arg Ser Lys Leu Glu 225 230 235 240 Pro Tyr Glu Tyr Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser                 245 250 255 Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu             260 265 270 Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys         275 280 285 Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg     290 295 300 Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser 305 310 315 320 Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile                 325 330 335 Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu             340 345 350 Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu         355 360 365 Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly     370 375 380 Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly 385 390 395 400 Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly                 405 410 415 Arg Thr Phe Ser Ser Tyr Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly             420 425 430 Lys Glu Arg Glu Tyr Val Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala         435 440 445 Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn     450 455 460 Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp 465 470 475 480 Thr Ala Val Tyr Tyr Cys Ala Asn Arg Ala Pro Asp Thr Arg Leu Ala                 485 490 495 Pro Tyr Glu Tyr Asp His Trp Gly Gln Gly Thr Leu Val Thr Val Ser             500 505 510 Ser      <210> 462 <211> 385 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 462 Asp Val Gln Leu Val Glu Ser Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr Glu Tyr Asp His             100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser         115 120 125 Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val     130 135 140 Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ser Ser Gly Phe Thr 145 150 155 160 Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly                 165 170 175 Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr             180 185 190 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys         195 200 205 Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala     210 215 220 Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly 225 230 235 240 Thr Leu Val Thr Val Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Ser                 245 250 255 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly             260 265 270 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Asp Tyr         275 280 285 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val     290 295 300 Ser Ser Ile Arg Asp Asn Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val 305 310 315 320 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr                 325 330 335 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys             340 345 350 Ala Ala Val Pro Ala Gly Arg Leu Arg Phe Gly Glu Gln Trp Tyr Pro         355 360 365 Leu Tyr Glu Tyr Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser     370 375 380 Ser 385 <210> 463 <211> 385 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 463 Asp Val Gln Leu Val Glu Ser Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Ser Ile Arg Asp Asn Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Val Pro Ala Gly Arg Leu Arg Phe Gly Glu Gln Trp Tyr Pro             100 105 110 Leu Tyr Glu Tyr Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser         115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu     130 135 140 Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys 145 150 155 160 Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg                 165 170 175 Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser             180 185 190 Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile         195 200 205 Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu     210 215 220 Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu 225 230 235 240 Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly                 245 250 255 Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly             260 265 270 Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly         275 280 285 Arg Thr Phe Ser Ser Tyr Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly     290 295 300 Lys Glu Arg Glu Tyr Val Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala 305 310 315 320 Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn                 325 330 335 Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp             340 345 350 Thr Ala Val Tyr Tyr Cys Ala Asn Arg Ala Pro Asp Thr Arg Leu Ala         355 360 365 Pro Tyr Glu Tyr Asp His Trp Gly Gln Gly Thr Leu Val Thr Val Ser     370 375 380 Ser 385 <210> 464 <211> 523 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 464 Asp Val Gln Leu Val Glu Ser Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr Glu Tyr Asp His             100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser         115 120 125 Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val     130 135 140 Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ser Ser Gly Phe Thr 145 150 155 160 Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly                 165 170 175 Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr             180 185 190 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys         195 200 205 Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala     210 215 220 Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly 225 230 235 240 Thr Leu Val Thr Val Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Ser                 245 250 255 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly             260 265 270 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Asp Tyr         275 280 285 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val     290 295 300 Ser Ser Ile Arg Asp Asn Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val 305 310 315 320 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr                 325 330 335 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys             340 345 350 Ala Ala Val Pro Ala Gly Arg Leu Arg Phe Gly Glu Gln Trp Tyr Pro         355 360 365 Leu Tyr Glu Tyr Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser     370 375 380 Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu 385 390 395 400 Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys                 405 410 415 Ala Ala Ser Gly Phe Thr Leu Asp Asp Tyr Ala Ile Gly Trp Phe Arg             420 425 430 Gln Ala Pro Gly Lys Glu Arg Glu Gly Val Ser Ser Ile Arg Asp Asn         435 440 445 Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile     450 455 460 Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu 465 470 475 480 Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Val Pro Ala Gly                 485 490 495 Arg Leu Arg Phe Gly Glu Gln Trp Tyr Pro Leu Tyr Glu Tyr Asp Ala             500 505 510 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser         515 520 <210> 465 <211> 382 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 465 Asp Val Gln Leu Val Glu Ser Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr Glu Tyr Asp His             100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser         115 120 125 Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val     130 135 140 Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ser Ser Gly Phe Thr 145 150 155 160 Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly                 165 170 175 Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr             180 185 190 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys         195 200 205 Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala     210 215 220 Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly 225 230 235 240 Thr Leu Val Thr Val Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Ser                 245 250 255 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly             260 265 270 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Leu Asp Tyr Tyr         275 280 285 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val     290 295 300 Ser Cys Ile Ser Ser Ser Asp Gly Ile Thr Tyr Tyr Ala Asp Ser Val 305 310 315 320 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr                 325 330 335 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys             340 345 350 Ala Thr Asp Ser Gly Gly Tyr Ile Asp Tyr Asp Cys Met Gly Leu Gly         355 360 365 Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser     370 375 380 <210> 466 <211> 382 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 466 Asp Val Gln Leu Val Glu Ser Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Leu Asp Tyr Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Gly Ile Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Asp Ser Gly Gly Tyr Ile Asp Tyr Asp Cys Met Gly Leu Gly             100 105 110 Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly         115 120 125 Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly     130 135 140 Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser 145 150 155 160 Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro                 165 170 175 Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp             180 185 190 Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp         195 200 205 Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu     210 215 220 Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser 225 230 235 240 Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly                 245 250 255 Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln             260 265 270 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe         275 280 285 Ser Ser Tyr Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg     290 295 300 Glu Tyr Val Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala 305 310 315 320 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn                 325 330 335 Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val             340 345 350 Tyr Tyr Cys Ala Asn Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr Glu         355 360 365 Tyr Asp His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser     370 375 380 <210> 467 <211> 523 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 467 Asp Val Gln Leu Val Glu Ser Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Ser Ile Arg Asp Asn Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Val Pro Ala Gly Arg Leu Arg Phe Gly Glu Gln Trp Tyr Pro             100 105 110 Leu Tyr Glu Tyr Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser         115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu     130 135 140 Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys 145 150 155 160 Ala Ala Ser Gly Phe Thr Leu Asp Asp Tyr Ala Ile Gly Trp Phe Arg                 165 170 175 Gln Ala Pro Gly Lys Glu Arg Glu Gly Val Ser Ser Ile Arg Asp Asn             180 185 190 Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile         195 200 205 Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu     210 215 220 Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Val Pro Ala Gly 225 230 235 240 Arg Leu Arg Phe Gly Glu Gln Trp Tyr Pro Leu Tyr Glu Tyr Asp Ala                 245 250 255 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser             260 265 270 Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val         275 280 285 Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ser Ser Gly Phe Thr     290 295 300 Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly 305 310 315 320 Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr                 325 330 335 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys             340 345 350 Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala         355 360 365 Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly     370 375 380 Thr Leu Val Thr Val Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Ser 385 390 395 400 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly                 405 410 415 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             420 425 430 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         435 440 445 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     450 455 460 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 465 470 475 480 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 485 490 495 Ala Asn Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr Glu Tyr Asp His             500 505 510 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser         515 520 <210> 468 <211> 513 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 468 Asp Val Gln Leu Val Glu Ser Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr Glu Tyr Asp His             100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser         115 120 125 Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val     130 135 140 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 145 150 155 160 Phe Asp Asp Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu                 165 170 175 Arg Glu Gly Val Ser Cys Ile Arg Cys Ser Asp Gly Ser Thr Tyr Tyr             180 185 190 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys         195 200 205 Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala     210 215 220 Val Tyr Tyr Cys Ala Ala Ser Ile Val Pro Arg Ser Lys Leu Glu Pro 225 230 235 240 Tyr Glu Tyr Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser                 245 250 255 Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser             260 265 270 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala         275 280 285 Ala Ser Gly Phe Thr Phe Asp Asp Tyr Ala Leu Gly Trp Phe Arg Gln     290 295 300 Ala Pro Gly Lys Glu Arg Glu Gly Val Ser Cys Ile Arg Cys Ser Asp 305 310 315 320 Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser                 325 330 335 Ser Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg             340 345 350 Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Ser Ile Val Pro Arg         355 360 365 Ser Lys Leu Glu Pro Tyr Glu Tyr Asp Ala Trp Gly Gln Gly Thr Leu     370 375 380 Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val 385 390 395 400 Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu                 405 410 415 Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met             420 425 430 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser         435 440 445 Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly     450 455 460 Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln 465 470 475 480 Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile                 485 490 495 Gly Gly Ser Ser Ser Ser Ser Ser Ser Gln Gly Thr Leu Val Thr Val Ser             500 505 510 Ser      <210> 469 <211> 513 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 469 Asp Val Gln Leu Val Glu Ser Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Arg Cys Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Ser Ile Val Pro Arg Ser Ser Lys Leu Glu Pro Tyr Glu Tyr Asp             100 105 110 Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly         115 120 125 Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu     130 135 140 Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ser Ser Gly Phe 145 150 155 160 Thr Phe Asp Asp Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys                 165 170 175 Glu Arg Glu Gly Val Ser Cys Ile Arg Cys Ser Asp Gly Ser Thr Tyr             180 185 190 Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser         195 200 205 Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr     210 215 220 Ala Val Tyr Tyr Cys Ala Ala Ser Ile Val Pro Arg Ser Lys Leu Glu 225 230 235 240 Pro Tyr Glu Tyr Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser                 245 250 255 Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu             260 265 270 Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys         275 280 285 Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr Ala Met Ala Trp Tyr Arg     290 295 300 Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val Ala Ala Ile Arg Trp Ser 305 310 315 320 Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile                 325 330 335 Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu             340 345 350 Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Asn Arg Ala Pro Asp         355 360 365 Thr Arg Leu Ala Pro Tyr Glu Tyr Asp His Trp Gly Gln Gly Thr Leu     370 375 380 Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val 385 390 395 400 Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu                 405 410 415 Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met             420 425 430 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser         435 440 445 Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly     450 455 460 Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln 465 470 475 480 Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile                 485 490 495 Gly Gly Ser Ser Ser Ser Ser Ser Ser Gln Gly Thr Leu Val Thr Val Ser             500 505 510 Ser      <210> 470 <211> 385 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 470 Asp Val Gln Leu Val Glu Ser Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr Glu Tyr Asp His             100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser         115 120 125 Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val     130 135 140 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 145 150 155 160 Leu Asp Asp Tyr Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu                 165 170 175 Arg Glu Gly Val Ser Ser Ile Arg Asp Asn Asp Gly Ser Thr Tyr Tyr             180 185 190 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys         195 200 205 Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala     210 215 220 Val Tyr Tyr Cys Ala Ala Val Pro Ala Gly Arg Leu Arg Phe Gly Glu 225 230 235 240 Gln Trp Tyr Pro Leu Tyr Glu Tyr Asp Ala Trp Gly Gln Gly Thr Leu                 245 250 255 Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val             260 265 270 Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu         275 280 285 Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met     290 295 300 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser 305 310 315 320 Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly                 325 330 335 Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln             340 345 350 Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile         355 360 365 Gly Gly Ser Ser Ser Ser Ser Ser Ser Gln Gly Thr Leu Val Thr Val Ser     370 375 380 Ser 385 <210> 471 <211> 385 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 471 Asp Val Gln Leu Val Glu Ser Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Ser Ile Arg Asp Asn Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Val Pro Ala Gly Arg Leu Arg Phe Gly Glu Gln Trp Tyr Pro             100 105 110 Leu Tyr Glu Tyr Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser         115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu     130 135 140 Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys 145 150 155 160 Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr Ala Met Ala Trp Tyr Arg                 165 170 175 Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val Ala Ala Ile Arg Trp Ser             180 185 190 Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile         195 200 205 Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu     210 215 220 Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Asn Arg Ala Pro Asp 225 230 235 240 Thr Arg Leu Ala Pro Tyr Glu Tyr Asp His Trp Gly Gln Gly Thr Leu                 245 250 255 Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val             260 265 270 Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu         275 280 285 Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met     290 295 300 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser 305 310 315 320 Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly                 325 330 335 Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln             340 345 350 Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile         355 360 365 Gly Gly Ser Ser Ser Ser Ser Ser Ser Gln Gly Thr Leu Val Thr Val Ser     370 375 380 Ser 385 <210> 472 <211> 523 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 472 Asp Val Gln Leu Val Glu Ser Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr Glu Tyr Asp His             100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser         115 120 125 Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val     130 135 140 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 145 150 155 160 Leu Asp Asp Tyr Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu                 165 170 175 Arg Glu Gly Val Ser Ser Ile Arg Asp Asn Asp Gly Ser Thr Tyr Tyr             180 185 190 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys         195 200 205 Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala     210 215 220 Val Tyr Tyr Cys Ala Ala Val Pro Ala Gly Arg Leu Arg Phe Gly Glu 225 230 235 240 Gln Trp Tyr Pro Leu Tyr Glu Tyr Asp Ala Trp Gly Gln Gly Thr Leu                 245 250 255 Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val             260 265 270 Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu         275 280 285 Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Asp Tyr Ala Ile     290 295 300 Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val Ser Ser 305 310 315 320 Ile Arg Asp Asn Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly                 325 330 335 Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln             340 345 350 Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala         355 360 365 Val Pro Ala Gly Arg Leu Arg Phe Gly Glu Gln Trp Tyr Pro Leu Tyr     370 375 380 Glu Tyr Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly 385 390 395 400 Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly                 405 410 415 Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala             420 425 430 Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala         435 440 445 Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser     450 455 460 Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg 465 470 475 480 Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro                 485 490 495 Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg             500 505 510 Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser         515 520 <210> 473 <211> 523 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 473 Asp Val Gln Leu Val Glu Ser Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Ser Ile Arg Asp Asn Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Val Pro Ala Gly Arg Leu Arg Phe Gly Glu Gln Trp Tyr Pro             100 105 110 Leu Tyr Glu Tyr Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser         115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu     130 135 140 Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys 145 150 155 160 Ala Ala Ser Gly Phe Thr Leu Asp Asp Tyr Ala Ile Gly Trp Phe Arg                 165 170 175 Gln Ala Pro Gly Lys Glu Arg Glu Gly Val Ser Ser Ile Arg Asp Asn             180 185 190 Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile         195 200 205 Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu     210 215 220 Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Val Pro Ala Gly 225 230 235 240 Arg Leu Arg Phe Gly Glu Gln Trp Tyr Pro Leu Tyr Glu Tyr Asp Ala                 245 250 255 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser             260 265 270 Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val         275 280 285 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr     290 295 300 Phe Ser Ser Tyr Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu 305 310 315 320 Arg Glu Tyr Val Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr                 325 330 335 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys             340 345 350 Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala         355 360 365 Val Tyr Tyr Cys Ala Asn Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr     370 375 380 Glu Tyr Asp His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly 385 390 395 400 Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly                 405 410 415 Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala             420 425 430 Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala         435 440 445 Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser     450 455 460 Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg 465 470 475 480 Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro                 485 490 495 Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg             500 505 510 Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser         515 520 <210> 474 <211> 382 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 474 Asp Val Gln Leu Val Glu Ser Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr Glu Tyr Asp His             100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser         115 120 125 Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val     130 135 140 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala 145 150 155 160 Leu Asp Tyr Tyr Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu                 165 170 175 Arg Glu Gly Val Ser Cys Ile Ser Ser Ser Asp Gly Ile Thr Tyr Tyr             180 185 190 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys         195 200 205 Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala     210 215 220 Val Tyr Tyr Cys Ala Thr Asp Ser Gly Gly Tyr Ile Asp Tyr Asp Cys 225 230 235 240 Met Gly Leu Gly Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val                 245 250 255 Ser Ser Gly Gly Gly Gly Ser Gly             260 265 270 Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser         275 280 285 Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val     290 295 300 Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly 305 310 315 320 Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr                 325 330 335 Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser             340 345 350 Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser         355 360 365 Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser     370 375 380 <210> 475 <211> 382 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 475 Asp Val Gln Leu Val Glu Ser Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Leu Asp Tyr Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Gly Ile Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Asp Ser Gly Gly Tyr Ile Asp Tyr Asp Cys Met Gly Leu Gly             100 105 110 Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly         115 120 125 Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly     130 135 140 Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser 145 150 155 160 Gly Arg Thr Phe Ser Ser Tyr Ala Met Ala Trp Tyr Arg Gln Ala Pro                 165 170 175 Gly Lys Glu Arg Glu Tyr Val Ala Ala Ile Arg Trp Ser Gly Gly Thr             180 185 190 Ala Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp         195 200 205 Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu     210 215 220 Asp Thr Ala Val Tyr Tyr Cys Ala Asn Arg Ala Pro Asp Thr Arg Leu 225 230 235 240 Ala Pro Tyr Glu Tyr Asp His Trp Gly Gln Gly Thr Leu Val Thr Val                 245 250 255 Ser Ser Gly Gly Gly Gly Ser Gly             260 265 270 Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser         275 280 285 Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val     290 295 300 Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly 305 310 315 320 Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr                 325 330 335 Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser             340 345 350 Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser         355 360 365 Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser     370 375 380 <210> 476 <211> 513 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 476 Asp Val Gln Leu Val Glu Ser Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr             20 25 30 Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val         35 40 45 Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Asn Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr Glu Tyr Asp His             100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser         115 120 125 Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val     130 135 140 Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ser Ser Gly Phe Thr 145 150 155 160 Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly                 165 170 175 Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr             180 185 190 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys         195 200 205 Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala     210 215 220 Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly 225 230 235 240 Thr Leu Val Thr Val Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Ser                 245 250 255 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly             260 265 270 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr         275 280 285 Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val     290 295 300 Ser Cys Ile Arg Cys Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 305 310 315 320 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr                 325 330 335 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys             340 345 350 Ala Ala Ser Ile Val Pro Arg Ser Ser Lys Leu Glu Pro Tyr Glu Tyr Asp         355 360 365 Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly     370 375 380 Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu 385 390 395 400 Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ser Ser Gly Phe                 405 410 415 Thr Phe Asp Asp Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys             420 425 430 Glu Arg Glu Gly Val Ser Cys Ile Arg Cys Ser Gly Gly Ser Thr Tyr         435 440 445 Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser     450 455 460 Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr 465 470 475 480 Ala Val Tyr Tyr Cys Ala Ala Ser Ile Val Pro Arg Ser Lys Leu Glu                 485 490 495 Pro Tyr Glu Tyr Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser             500 505 510 Ser      <210> 477 <211> 385 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 477 Asp Val Gln Leu Val Glu Ser Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Thr Leu Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Ala Ile Arg Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Val Pro Ala Gly Arg Leu Arg Tyr Gly Glu Gln Trp Tyr Pro             100 105 110 Ile Tyr Glu Tyr Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser         115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu     130 135 140 Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys 145 150 155 160 Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr Ala Met Ala Trp Tyr Arg                 165 170 175 Gln Ala Pro Gly Lys Glu Arg Glu Tyr Val Ala Ala Ile Arg Trp Ser             180 185 190 Gly Gly Thr Ala Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile         195 200 205 Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu     210 215 220 Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Asn Arg Ala Pro Asp 225 230 235 240 Thr Arg Leu Ala Pro Tyr Glu Tyr Asp His Trp Gly Gln Gly Thr Leu                 245 250 255 Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val             260 265 270 Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu         275 280 285 Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met     290 295 300 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser 305 310 315 320 Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly                 325 330 335 Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln             340 345 350 Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile         355 360 365 Gly Gly Ser Ser Ser Ser Ser Ser Ser Gln Gly Thr Leu Val Thr Val Ser     370 375 380 Ser 385 <210> 478 <211> 523 <212> PRT <213> Artificial <220> <223> Mutated Lama sequence <400> 478 Asp Val Gln Leu Val Glu Ser Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Ala Ile Arg Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Val Pro Ala Gly Arg Leu Arg Phe Gly Glu Gln Trp Tyr Pro             100 105 110 Leu Tyr Glu Tyr Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser         115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu     130 135 140 Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys 145 150 155 160 Ala Ala Ser Gly Phe Thr Leu Asp Asp Tyr Ala Ile Gly Trp Phe Arg                 165 170 175 Gln Ala Pro Gly Lys Glu Arg Glu Gly Val Ser Ala Ile Arg Ser Ser             180 185 190 Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile         195 200 205 Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu     210 215 220 Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Val Pro Ala Gly 225 230 235 240 Arg Leu Arg Phe Gly Glu Gln Trp Tyr Pro Leu Tyr Glu Tyr Asp Ala                 245 250 255 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser             260 265 270 Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val         275 280 285 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr     290 295 300 Phe Ser Ser Tyr Ala Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Glu 305 310 315 320 Arg Glu Tyr Val Ala Ala Ile Arg Trp Ser Gly Gly Thr Ala Tyr Tyr                 325 330 335 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys             340 345 350 Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala         355 360 365 Val Tyr Tyr Cys Ala Asn Arg Ala Pro Asp Thr Arg Leu Ala Pro Tyr     370 375 380 Glu Tyr Asp His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly 385 390 395 400 Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly                 405 410 415 Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala             420 425 430 Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala         435 440 445 Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser     450 455 460 Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg 465 470 475 480 Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro                 485 490 495 Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg             500 505 510 Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser         515 520 <210> 479 <211> 124 <212> PRT <213> Lama glama <400> 479 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Leu Gly Trp Phe Arg Gln Ala Ala Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Arg Cys Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Ser Ile Val Pro Arg Ser Ser Lys Leu Glu Pro Tyr Glu Tyr Asp             100 105 110 Ala Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 <210> 480 <211> 126 <212> PRT <213> Lama glama &Lt; 400 > 480 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Leu Asp Tyr Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Val Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Gly Ile Thr Tyr Tyr Val Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Asp Ser Gly Gly Tyr Ile Asp Tyr Asp Cys Met Gly Leu Gly             100 105 110 Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser         115 120 125 <210> 481 <211> 129 <212> PRT <213> Lama glama <400> 481 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Arg Asp Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Asp Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Val Pro Ala Gly Arg Leu Arg Phe Gly Glu Gln Trp Tyr Pro             100 105 110 Leu Tyr Glu Tyr Asp Ala Trp Gly Gln Gly Thr Gln Val Thr Val Ser         115 120 125 Ser      <210> 482 <211> 129 <212> PRT <213> Artificial <220> <223> Mutated lama sequence <400> 482 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Ser Ile Arg Asp Asn Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Val Pro Ala Gly Arg Leu Arg Phe Gly Glu Gln Trp Tyr Pro             100 105 110 Leu Tyr Glu Tyr Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser         115 120 125 Ser      <210> 483 <211> 124 <212> PRT <213> Artificial <220> <223> Mutated lama sequence <400> 483 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Arg Cys Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Ser Ile Val Pro Arg Ser Ser Lys Leu Glu Pro Tyr Glu Tyr Asp             100 105 110 Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser         115 120 <210> 484 <211> 126 <212> PRT <213> Artificial <220> <223> Mutated lama sequence <400> 484 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Leu Asp Tyr Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Ser Asp Gly Ile Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Asp Ser Gly Gly Tyr Ile Asp Tyr Asp Cys Met Gly Leu Gly             100 105 110 Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser         115 120 125 <210> 485 <211> 124 <212> PRT <213> Artificial <220> <223> Mutated lama sequence <400> 485 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr             20 25 30 Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Arg Cys Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Ser Ile Val Pro Arg Ser Ser Lys Leu Glu Pro Tyr Glu Tyr Asp             100 105 110 Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser         115 120 <210> 486 <211> 126 <212> PRT <213> Artificial <220> <223> Mutated lama sequence <400> 486 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Leu Asp Tyr Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Cys Ile Ser Ser Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Asp Ser Gly Gly Tyr Ile Asp Tyr Asp Cys Ser Gly Leu Gly             100 105 110 Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser         115 120 125 <210> 487 <211> 129 <212> PRT <213> Artificial <220> <223> Mutated lama sequence <400> 487 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Thr Leu Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Ala Ile Arg Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Val Pro Ala Gly Arg Leu Arg Tyr Gly Glu Gln Trp Tyr Pro             100 105 110 Ile Tyr Glu Tyr Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser         115 120 125 Ser      <210> 488 <211> 129 <212> PRT <213> Artificial <220> <223> Mutated lama sequence <400> 488 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Asp Tyr             20 25 30 Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val         35 40 45 Ser Ala Ile Arg Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Ala Val Pro Ala Gly Arg Leu Arg Phe Gly Glu Gln Trp Tyr Pro             100 105 110 Leu Tyr Glu Tyr Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser         115 120 125 Ser      <210> 489 <211> 5 <212> PRT <213> Lama glama <400> 489 Asp Tyr Ala Leu Gly 1 5 <210> 490 <211> 17 <212> PRT <213> Lama glama <400> 490 Cys Ile Arg Cys Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly      <210> 491 <211> 15 <212> PRT <213> Lama glama <400> 491 Ser Ile Val Pro Arg Ser Ser Lys Leu Glu Pro Tyr Glu Tyr Asp Ala 1 5 10 15 <210> 492 <211> 5 <212> PRT <213> Lama glama <400> 492 Tyr Tyr Ala Ile Gly 1 5 <210> 493 <211> 17 <212> PRT <213> Lama glama <400> 493 Cys Ile Ser Ser Ser Asp Gly Ile Thr Tyr Tyr Val Asp Ser Val Lys 1 5 10 15 Gly      <210> 494 <211> 17 <212> PRT <213> Lama glama <400> 494 Asp Ser Gly Gly Tyr Ile Asp Tyr Asp Cys Met Gly Leu Gly Tyr Asp 1 5 10 15 Tyr      <210> 495 <211> 5 <212> PRT <213> Lama glama <400> 495 Asp Tyr Ala Ile Gly 1 5 <210> 496 <211> 17 <212> PRT <213> Lama glama <400> 496 Cys Ile Arg Asp Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly      <210> 497 <211> 20 <212> PRT <213> Lama glama <400> 497 Val Pro Ala Gly Arg Leu Arg Phe Gly Glu Gln Trp Tyr Pro Leu Tyr 1 5 10 15 Glu Tyr Asp Ala             20 <210> 498 <211> 5 <212> PRT <213> Lama glama <400> 498 Asp Tyr Ala Ile Gly 1 5 <210> 499 <211> 17 <212> PRT <213> Lama glama <400> 499 Ser Ile Arg Asp Asn Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly      <210> 500 <211> 20 <212> PRT <213> Lama glama <400> 500 Val Pro Ala Gly Arg Leu Arg Phe Gly Glu Gln Trp Tyr Pro Leu Tyr 1 5 10 15 Glu Tyr Asp Ala             20 <210> 501 <211> 5 <212> PRT <213> Lama glama <400> 501 Asp Tyr Ala Leu Gly 1 5 <210> 502 <211> 17 <212> PRT <213> Lama glama <400> 502 Cys Ile Arg Cys Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly      <210> 503 <211> 15 <212> PRT <213> Lama glama <400> 503 Ser Ile Val Pro Arg Ser Ser Lys Leu Glu Pro Tyr Glu Tyr Asp Ala 1 5 10 15 <210> 504 <211> 5 <212> PRT <213> Lama glama <400> 504 Tyr Tyr Ala Ile Gly 1 5 <210> 505 <211> 17 <212> PRT <213> Lama glama <400> 505 Cys Ile Ser Ser Ser Asp Gly Ile Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly      <210> 506 <211> 17 <212> PRT <213> Lama glama <400> 506 Asp Ser Gly Gly Tyr Ile Asp Tyr Asp Cys Met Gly Leu Gly Tyr Asp 1 5 10 15 Tyr      <210> 507 <211> 5 <212> PRT <213> Lama glama <400> 507 Asp Tyr Ala Leu Gly 1 5 <210> 508 <211> 17 <212> PRT <213> Lama glama <400> 508 Cys Ile Arg Cys Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly      <210> 509 <211> 15 <212> PRT <213> Lama glama <400> 509 Ser Ile Val Pro Arg Ser Ser Lys Leu Glu Pro Tyr Glu Tyr Asp Ala 1 5 10 15 <210> 510 <211> 5 <212> PRT <213> Lama glama <400> 510 Tyr Tyr Ala Ile Gly 1 5 <210> 511 <211> 17 <212> PRT <213> Lama glama <400> 511 Cys Ile Ser Ser Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly      <210> 512 <211> 17 <212> PRT <213> Artificial <220> <223> Mutated lama sequence <400> 512 Asp Ser Gly Gly Tyr Ile Asp Tyr Asp Cys Ser Gly Leu Gly Tyr Asp 1 5 10 15 Tyr      <210> 513 <211> 5 <212> PRT <213> Lama glama <400> 513 Asp Tyr Ala Ile Gly 1 5 <210> 514 <211> 17 <212> PRT <213> Artificial <220> <223> Mutated lama sequence <400> 514 Ala Ile Arg Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly      <210> 515 <211> 20 <212> PRT <213> Artificial <220> <223> Mutated lama sequence <400> 515 Val Pro Ala Gly Arg Leu Arg Tyr Gly Glu Gln Trp Tyr Pro Ile Tyr 1 5 10 15 Glu Tyr Asp Ala             20 <210> 516 <211> 5 <212> PRT <213> Lama glama <400> 516 Asp Tyr Ala Ile Gly 1 5 <210> 517 <211> 17 <212> PRT <213> Artificial <220> <223> Mutated lama sequence <400> 517 Ala Ile Arg Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly      <210> 518 <211> 20 <212> PRT <213> Artificial <220> <223> Mutated lama sequence <400> 518 Val Pro Ala Gly Arg Leu Arg Phe Gly Glu Gln Trp Tyr Pro Leu Tyr 1 5 10 15 Glu Tyr Asp Ala             20 <210> 519 <211> 115 <212> PRT <213> Artificial <220> <223> Mutated lama sequence <400> 519 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe             20 25 30 Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr             100 105 110 Val Ser Ser         115 <210> 520 <211> 5 <212> PRT <213> Lama glama <400> 520 Ser Phe Gly Met Ser 1 5 <210> 521 <211> 17 <212> PRT <213> Lama glama <400> 521 Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly      <210> 522 <211> 6 <212> PRT <213> Lama glama <400> 522 Gly Gly Ser Leu Ser Arg 1 5 <210> 523 <211> 5 <212> PRT <213> Lama glama <400> 523 Leu Asn Leu Met Gly 1 5 <210> 524 <211> 16 <212> PRT <213> Lama glama <400> 524 Thr Ile Thr Val Gly Asp Ser Thr Asn Tyr Ala Asp Ser Val Lys Gly 1 5 10 15 <210> 525 <211> 8 <212> PRT <213> Lama glama <400> 525 Arg Arg Thr Trp His Ser Glu Leu 1 5 <210> 526 <211> 5 <212> PRT <213> Lama glama <400> 526 Ile Asn Leu Leu Gly 1 5 <210> 527 <211> 16 <212> PRT <213> Lama glama <400> 527 Thr Ile Thr Val Gly Asp Ser Thr Ser Tyr Ala Asp Ser Val Lys Gly 1 5 10 15 <210> 528 <211> 8 <212> PRT <213> Lama glama <400> 528 Arg Arg Thr Trp His Ser Glu Leu 1 5 <210> 529 <211> 5 <212> PRT <213> Lama glama <400> 529 Ser Phe Gly Met Ser 1 5 <210> 530 <211> 17 <212> PRT <213> Lama glama &Lt; 400 > 530 Ser Ile Asn Gly Arg Gly Asp Asp Thr Arg Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly      <210> 531 <211> 7 <212> PRT <213> Lama glama <400> 531 Gly Arg Ser Val Ser Arg Ser 1 5 <210> 532 <211> 5 <212> PRT <213> Lama glama <400> 532 Ser Phe Gly Met Ser 1 5 <210> 533 <211> 17 <212> PRT <213> Lama glama <400> 533 Ala Ile Ser Ala Asp Ser Ser Asp Lys Arg Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly      <210> 534 <211> 5 <212> PRT <213> Lama glama <400> 534 Gly Arg Gly Ser Pro 1 5 <210> 535 <211> 5 <212> PRT <213> Lama glama <400> 535 Ser Phe Gly Met Ser 1 5 <210> 536 <211> 17 <212> PRT <213> Lama glama <400> 536 Ala Ile Ser Ala Asp Ser Ser Asp Lys Arg Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly      <210> 537 <211> 5 <212> PRT <213> Lama glama <400> 537 Gly Arg Gly Ser Pro 1 5 <210> 538 <211> 5 <212> PRT <213> Lama glama <400> 538 Asn Tyr Trp Met Tyr 1 5 <210> 539 <211> 17 <212> PRT <213> Lama glama <400> 539 Arg Ile Ser Thr Gly Gly Gly Tyr Ser Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly      <210> 540 <211> 13 <212> PRT <213> Lama glama <540> 540 Asp Arg Glu Ala Gln Val Asp Thr Leu Asp Phe Asp Tyr 1 5 10

Claims (42)

A bispecific binding molecule comprising at least one Ang 2 -binding component and at least one Dll 4 -binding component. The bispecific binding molecule of claim 1, further comprising at least one serum albumin binding component. The Dll4 binding according to claim 1 or 2, comprising at least one variable domain each having four framework regions and three complementarity determining regions CDR1, CDR2 and CDR3 of an amino acid sequence selected from the amino acid sequences shown below. Bispecific binding molecules containing components:
a. SEQ ID NOs: 1 to 166 and 458,
b. SEQ ID NOs: 333 to 353, or
c. SEQ ID NOs: 375 to 395. The method of claim 3, wherein the Dll4-binding component is an isolated immunoglobulin single variable domain or a polypeptide containing one or more of said immunoglobulin single variable domains, wherein the immunoglobulin single variable domain is comprised of four framework regions and three complementarities. Bispecific binding molecules, each consisting of the determining regions CDR1, CDR2 and CDR3 of the amino acid sequence selected from the amino acid sequences shown below:
a. SEQ ID NOs: 1 to 166 and 458,
b. SEQ ID NOs: 333 to 353, or
c. SEQ ID NOs: 375 to 395. The method of claim 4, wherein the one or more immunoglobulin single variable domains are
a. A CDR3 having an amino acid sequence selected from the first group of amino acid sequences shown as SEQ ID NOs: 1-166;
b. As shown in Table 5, it contains CDR1 and CDR2 having amino acid sequences contained in a sequence selected from the second group of amino acid sequences shown in SEQ ID NOs: 167 to 332 and 459 as partial sequences,
c. Wherein the bispecific binding molecule of SEQ ID NO: 1-166 corresponds to SEQ ID NO: y of the second group in that y = x + 166. The method of claim 4, wherein the one or more immunoglobulin single variable domains are
a. A CDR3 having an amino acid sequence selected from the first group of amino acid sequences shown as SEQ ID NOs: 333 to 353;
b. As described in Table 16-A, contains as partial sequences CDR1 and CDR2 having amino acid sequences contained within a sequence selected from the second group of sequences shown in SEQ ID NOs: 354-374,
c. Wherein the first group of SEQ ID NO: x corresponds to the second group of SEQ ID NO: y in that y = x + 21. The method of claim 4, wherein the one or more immunoglobulin single variable domains are
a. A CDR3 having an amino acid sequence selected from the first group of amino acid sequences shown as SEQ ID NOs: 375 to 395;
b. As described in Table 16-B, contains as partial sequences CDR1 and CDR2 having amino acid sequences contained within a sequence selected from the second group of sequences shown in SEQ ID NOs: 396-416,
c. Wherein the first group of SEQ ID NO: x corresponds to the second group of SEQ ID NO: y in that y = x + 21. 8. The bispecific binding molecule of claim 4, wherein at least one immunoglobulin single variable domain is VHH. 9. The bispecific binding molecule of claim 8, wherein at least one VHH has an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 167-332 and 459. The bispecific binding molecule of claim 8, wherein at least one VHH has an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 354-374. The bispecific binding molecule of claim 8, wherein at least one VHH has an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 396-416. An immunoglobulin single variable domain obtained by affinity maturation of an immunoglobulin single variable domain as defined in claim 5. VHH obtained by affinity maturation of VHH as defined in claim 9. Dll4-binding VHH having an amino acid sequence selected from amino acid sequences set forth in SEQ ID NOs: 356 and 358. An immunoglobulin single variable domain obtained by humanization of VHH as defined in claim 14. Dll4-binding VHH having an amino acid sequence selected from the sequences shown in SEQ ID NOs: 402, 407, and 416. An immunoglobulin single variable domain obtained by humanization of VHH as defined in claim 16. An immunoglobulin single variable domain obtained by humanization of an immunoglobulin single variable domain as defined in claim 5. An immunoglobulin single variable domain obtained by humanization of an immunoglobulin single variable domain as defined in claim 12. 2. The bispecific binding molecule of claim 1, which binds to an epitope of Dll4 contained in whole or in part in the EGF-2 domain corresponding to amino acid residues 252-282 of SEQ ID NO: 417. The bispecific binding molecule of claim 20, which is an immunoglobulin single variable domain or a polypeptide comprising the same. 21. The framework of claim 1, wherein the four framework regions and three complementarity determining regions CDR1, CDR2 and SEQ ID NOs: 491, 494, 497, 500, 503, 506, 509, 512, A bispecific binding molecule comprising an Ang2-binding component comprising at least one variable domain having each of CDR3 of the amino acid sequence selected from amino acid sequence 515, or 518. 23. The polypeptide of claim 22 wherein the Ang2-binding component is a polypeptide containing an isolated immunoglobulin single variable domain or one or more immunoglobulin single variable domains, wherein the immunoglobulin single variable domain comprises four framework regions and three complementarity determinations. A bispecific binding molecule consisting of regions CDR1, CDR2 and each of CDR3 of an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 491, 494, 497, 500, 503, 506, 509, 512, 515, or 518. The bispecific binding molecule of claim 23, wherein the one or more immunoglobulin single variable domains comprise:
a. CDR3 having an amino acid sequence selected from the first group of amino acid sequences shown in SEQ ID NOs: 491, 494, 497, 500, 503, 506, 509, 512, 515, or 518 (Table 36);
b. As described in Table 22-A or 28, as a partial sequence in the second group of amino acid sequences shown in SEQ ID NOs: 489, 492, 495, 498, 501, 504, 507, 510, 513, or 516 (Table 36) CDR1 having an amino acid sequence contained within the selected sequence;
c. As described in Table 22-A or 28, in the second group of amino acid sequences shown in SEQ ID NOs: 490, 493, 496, 499, 502, 505, 508, 511, 514, or 517 (Table 36) as partial sequences CDR2 having an amino acid sequence contained within a selected sequence. 25. The bispecific binding molecule of any one of claims 22 to 24, wherein the one or more immunoglobulin single variable domains is VHH. The bispecific binding molecule of claim 25, wherein the one or more VHHs have an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 479, 480, 481, 482, 483, 484, 485, 486, 487, or 488. An immunoglobulin single variable domain obtained by affinity maturation of an immunoglobulin single variable domain as defined in claim 24. VHH obtained by affinity maturation of VHH as defined in claim 26. Ang2-binding VHH having an amino acid sequence selected from amino acid sequences as set forth in SEQ ID NOs: 479, 480, 481, 482, 483, 484, 485, 486, 487, or 488. An immunoglobulin single variable domain obtained by humanization of VHH as defined in claim 29. An immunoglobulin single variable domain obtained by humanization of an immunoglobulin single variable domain as defined in claim 24. 32. The method according to any one of claims 2 to 31 wherein the serum albumin binding component is an isolated immunoglobulin single variable domain, or a polypeptide containing one or more immunoglobulin single variable domains, wherein the immunoglobulin single variable domain is A binding molecule consisting of each of the four framework regions and three complementarity determining regions CDR1, CDR2 and CDR3 of the amino acid sequence selected from the amino acid sequences shown in SEQ ID NOs: 522, 525, 528, 531, 534, 537, or 540. 33. The binding molecule of claim 32, wherein the one or more immunoglobulin single variable domains contain:
a. A CDR3 having an amino acid sequence selected from the first group of amino acid sequences set forth in SEQ ID NOs: 522, 525, 528, 531, 534, 537, or 540;
b. CDR1 having an amino acid sequence selected from the second group of amino acid sequences shown as SEQ ID NOs: 520, 523, 526, 529, 532, 535, or 538;
c. A CDR2 having an amino acid sequence selected from the second group of amino acid sequences shown as SEQ ID NOs: 521, 524, 527, 530, 533, 536, or 539. 34. The bispecific binding molecule of claim 32 or 33, wherein the at least one immunoglobulin single variable domain is VHH. 35. The bispecific binding molecule of claim 34, wherein at least one VHH has an amino acid sequence as set forth in SEQ ID NO: 98 or 519. 36. A bispecific binding molecule according to any one of claims 2 to 35, having an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 460 to 478. A nucleic acid molecule encoding the binding molecule of any one of claims 1 to 36 or a vector containing the same. A host cell containing the nucleic acid molecule of claim 37. A pharmaceutical composition comprising at least one of the bispecific binding molecules of claim 1 as an active ingredient. The pharmaceutical composition of claim 39 for the treatment of a disease associated with a Dll4-mediated and / or Ang2-mediated effect on angiogenesis. 41. The pharmaceutical composition of claim 40 for the treatment of cancer and cancerous diseases. The pharmaceutical composition of claim 39 for the treatment of eye diseases.

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